Compounds of GCN2 modulators

Abstract

The disclosures herein relate to compounds of Formula (I). or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein variables are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with General Control Nondepressible 2 (GCN2).

Description

COMPOUNDS OF GCN2 MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of United States Provisional Patent Application Nos.63 / 588,632, filed October 6, 2023, and 63 / 691,758, filed September 6, 2024. The disclosures of those applications are hereby incorporated herein by reference in their entirety. FIELD OF THE INVENTION

[0002] This application relates to novel compounds and their use as General Control Nondepressible 2 (GCN2) modulators. Compounds described herein may be useful in the treatment or prevention of diseases in which GCN2 is involved. BACKGROUND

[0003] Diverse cellular conditions and stresses activate a widely conserved signalling pathway termed the Integrated Stress Response (ISR) pathway. The activation of ISR can trigger cell-cycle arrest, differentiation, amino acid biosynthetic and transport pathways, compensatory adaptation, or apoptosis, depending on the cell type and the initiating stress. General Control.

[0004] Nonderepressible 2 (GCN2) is one of four stress kinases of the ISR pathway that senses amino acid availability and controls gene expression in response to amino acid deprivation, UV-irradiation, viral infection, proteasome inhibition, hypoxia, glucose deprivation and oxidative stress. In mammals, GCN2 is also called EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4).

[0005] GCN2 harbours a eukaryotic kinase domain, a pseudo-kinase domain and a histidyl-tRNA synthetase (HisRS)-related domain, which binds uncharged tRNAs with higher affinity than it does charged tRNAs. Sequences at both the N- and C-termini of GCN2 have been shown to be important for efficient sensing of the starvation signal. Lysine residues in the C-terminus have also been shown to be required for tRNA binding and kinase activity andresidues at the tip of the C-terminal region confer ribosome binding capabilities on GCN2, which are important for translational control.

[0006] In eukaryotes, the mechanism for recognizing indispensable amino acid deficiency follows the conserved general control system, wherein uncharged transfer RNA induces first the autophosphorylation of GCN2 and then the phosphorylation of eukaryotic initiation factor 2α (eIF2α), leading to reduced global protein synthesis and thus to reduced overall utilization of amino acids. Simultaneously, a group of stress-responsive mRNAs with upstream open reading frames (uORF) that include ATF4, CHOP, GADD34 and the (β-secretase BACE-1, are translated more efficiently when eIF2α is phosphorylated, which in turn increases amino acid biosynthetic and transport pathways. GCN2-mediated translational program also controls host responses to infection, responses to immunization, inflammation and other physiological and pathological processes. A significant subset of the genes upregulated by ATF4 are involved in amino acid import and metabolism and a hallmark of ATF4- / -cells is their impaired metabolism of amino acids.

[0007] Therefore, modulation of general control nonderepressible 2 (GCN2) may provide a therapeutic strategy for many diseases. SUMMARY OF THE INVENTION

[0008] The present invention provides compounds having activity as general control nonderepressible 2 (GCN2) modulators.

[0009] In one aspect, the invention provides a compound of Formula (I): RR R (I); or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, C6-C14aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, and 5- to 10- membered heteroaryl are each independently optionally substituted by one or more RL; R2, R8, R9and R10are independently H, halo, C1-C6 alkyl, or C1-C6 alkoxy; R3, R4, R5, R6and R7are independently selected from the group consisting of H, halo, -OR11, C1-C6alkyl, and C1-C6alkoxy; X and Y are each independently CRaRb, C=O, or O, wherein Raand Rbare each independently H, halo, -OR11, -NR12R13, C1-C6 alkyl optionally substituted by halo, or C1-C6 alkoxy optionally substituted by halo; Rcis H or OH; n is 1 or 2; each RLis independently selected from the group consisting of halo, -OR11, C1-C6 alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, C6- C14 aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and -NR12R13, wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13; R11is H or C1-C6alkyl optionally substituted by halo; and R12and R13, independently of each other and independently at each occurrence, are H or C1-C6 alkyl optionally substituted by C1-C6 alkoxy, halo, or -OH.

[0010] Compounds of the present invention may be used as GCN2 modulators. Compounds of the present invention may be used as GCN2 inhibitors. In addition to GCN2, there are other eIF2α kinases family including PKR-like endoplasmic reticulum (ER) kinase (PERK / EIF2AK3). In some embodiments, the compounds of the present invention decrease the activity of PERK.

[0011] Compounds of the present invention may be used as GCN2 antagonists. Compounds of the present invention may be used as GCN2 agonists. Compounds of the present invention may be used in the treatment of a disease or disorder characterised by activation of GCN2.

[0012] Compounds of the present invention may be used in the manufacture of medicaments. The compounds or medicaments may be for use in treating, preventing, ameliorating controlling or reducing the risk of diseases or disorders in which GCN2 isinvolved. Compounds of the present invention may be for use as a single agent or in combination with one or more additional pharmaceutical agents. Additional pharmaceutical agents may include radiotherapy, chemotherapy, immunotherapy or tumor microenvironment modulating agents.

[0013] Compounds of the present invention may be useful in the treatment of cancer, neurodegenerative diseases, chronic infections or conditions or symptoms related thereto. Compounds of the present invention may be useful in the treatment of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, cancer of secretory cells, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia. small cell lung cancer, malignant pleural mesothelioma, Head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma, pediatric neuroblastoma or symptoms related thereto.

[0014] Also provided herein is a method of treating a cancer in an individual comprising administering a compound of the present invention to the individual, wherein the cancer has a low level of expression or activity of a urea cycle enzyme. In some embodiments, provided herein is a method of treating cancer in an individual comprising (a) detecting the level of expression or activity of a urea cycle enzyme, and (b) administering a compound of the present invention to the individual if the cancer expresses a low level of expression or activity of a urea cycle enzyme. In some embodiments, provided herein is method of inhibiting tumor growth in an individual comprising administering a compound of the present invention to the individual, wherein the tumor has a low level of expression or activity of a urea cycle enzyme. In some embodiments, an effective amount of the compound is administered. In some embodiments, the urea cycle enzyme is argininosuccinate synthase 1 (ASS1).DETAILED DESCRIPTION OF THE INVENTION

[0015] The invention relates to novel compounds. The invention also relates to the use of novel compounds as modulators of GCN2. The invention further relates to the use of novel compounds in the manufacture of medicaments for use as GCN2 modulators.

[0016] The invention further relates to compounds, compositions and medicaments that may be useful in the treatment of cancer, neurodegenerative diseases, chronic infections or conditions or symptoms related thereto. Definitions

[0017] In this application, the following definitions apply, unless indicated otherwise.

[0018] The term “GCN2 modulator” as used herein refers to any compound which binds to and modulates the function of GCN2. The term “modulator” should be interpreted to include modulation by modalities including, but not limited to, antagonists, agonists, partial agonists and inverse agonists.

[0019] The term “treatment”, in relation to the uses of any of the compounds described herein, including those of Formula (I) is used to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question, such as cancer or an immunological disease. Thus, the term “treatment” covers both preventative (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being displayed. Treatment also encompasses decreasing one or more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a patient.

[0020] In some variations, treatment does not include prevention. Thus, it is understood that in some variations, treatment refers to uses of any of the compounds described herein, including those of Formula (I) is used to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question, such as cancer or an immunological disease.

[0021] “Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human.

[0022] The term “effective therapeutic amount” (for example in relation to methods of treatment of a disease or condition) refers to an amount of the compound which is effective to produce a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief may be, for example, complete removal of the pain or a reduction in the severity of the pain. With respect to the treatment, if the condition is cancer, then the effective therapeutic amount is an amount sufficient to reduce one or more symptoms associated with cancer, for example reduction of tumour size or rate of metastasis.

[0023] As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se.

[0024] “Alkyl” as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”), having 1 to 10 carbon atoms (a “C1-C10alkyl”), having 6 to 10 carbon atoms (a “C6-C10alkyl”), having 1 to 6 carbon atoms (a “C1-C6alkyl”), having 2 to 6 carbon atoms (a “C2-C6alkyl”), or having 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0025] “Alkenyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 6 to 10 carbon atoms (a “C6-C10 alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4alkenyl”). Examples of alkenyl group include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2- methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.

[0026] “Alkynyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2- C20alkynyl”), having 6 to 10 carbon atoms (a “C6-C10alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2- ynyl, but-3-ynyl, and the like.

[0027] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"), having 3 to 6 carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a "C3-C4cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0028] “Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C3-C10means three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-C8cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0029] “Aryl” or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C6-C14 aryl”). An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

[0030] “Heteroaryl” as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. Particular heteroaryl groups are 5- to 14- membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-, 6- or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7- membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atomsand 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heteroaryl group may be fused with aryl, cycloalkyl, or heterocyclyl. In one variation, a heteroaryl group having more than one ring where at least one ring is aryl, cycloalkyl, or heterocyclyl is connected to the parent structure at an atom in the aromatic cyclic group having at least one annular heteroatom. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0031] “Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. In certain embodiments, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for N-oxide, -S(O)-, or –SO2- moieties. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof, but excludes heteroaryl. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are 3- to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3- to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heterocyclyl group may be fused with aryl, cycloalkyl, or heteroaryl. In one variation, a heterocyclyl group having more than one ring where at least one ring is aryl, cycloalkyl, or heteroaryl is connected to the parent structure at an atom in the non-aromatic cyclic group having at least one heteroatom.

[0032] “Alkoxy” or “alkoxyl” as used herein refers to refers to an -O-alkyl moiety. As used herein, alkoxy has, for example, 1-6 carbons (i.e., C1-C6alkoxy), or 1-3 carbons (i.e., C1-C3 alkoxy). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.

[0033] “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3- fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (–OCF3).

[0034] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted.

[0035] To the extent that any of the compounds described have chiral centres, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. Also provided herein are, where applicable, any and all stereoisomers of the compounds depicted herein, including geometric isomers (e.g., cis / trans isomers or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio, including racemic mixtures.

[0036] The invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared. To the extent that any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt.

[0037] Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

[0038] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium.

[0039] Examples of acid addition salts include acid addition salts formed with acetic, 2,2- dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2- sulfonic, naphthalene-1,5-disulfonic and p-toluenesulfonic), ascorbic (e.g. L-ascorbic), L- aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)- camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g. (-)-L- malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic, 1-hydroxy-2- naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g.(+)-L-tartaric), thiocyanic, undecylenic and valeric acids.

[0040] Also encompassed are any solvates of the compounds and their salts. Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystalstructure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography.

[0041] The solvates can be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates. For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al, Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0042] The term “pharmaceutical composition” in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers that is suitable for administration to an individual. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations.

[0043] The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. In an analogous manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example a reference to an alkyl group such as an ethyl group or an alkoxy group such as amethoxy group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group) or a methoxy group in which all three hydrogen atoms are in the deuterium isotopic form (a trideuteromethoxy group). The isotopes may be radioactive or non-radioactive.

[0044] Therapeutic dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with the smaller dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0045] The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. The selection of appropriate dosages is within the ability of one of ordinary skill in this art, without undue burden. In general, the daily dose range may be from about 10 μg to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 μg to about 30 mg per kg of body weight of a human and non- human animal, for example from about 50 μg to about 10 mg per kg of body weight of a human and non-human animal, for example from about 100 μg to about 30 mg per kg of body weight of a human and non-human animal, for example from about 100 μg to about 10 mg per kg of body weight of a human and non-human animal and most preferably from about 100 μg to about 1 mg per kg of body weight of a human and non-human animal. Compounds

[0046] In one aspect, provided is a compound of Formula (I): RR6R7(I);or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C8cycloalkyl, C3-C8cycloalkenyl, C6-C14aryl, 3- to 12-membered heterocyclyl, and 5- to 10- membered heteroaryl are each independently optionally substituted by one or more RL; R2, R8, R9and R10are independently H, halo, C1-C6 alkyl, or C1-C6 alkoxy; R3, R4, R5, R6and R7are independently selected from the group consisting of H, halo, -OR11, C1-C6alkyl, and C1-C6alkoxy; X and Y are each independently CRaRb, C=O, or O, wherein Raand Rbare each independently H, halo, -OR11, -NR12R13, C1-C6 alkyl optionally substituted by halo, or C1-C6 alkoxy optionally substituted by halo; and Rcis H or OH; n is 1 or 2; each RLis independently selected from the group consisting of halo, -OR11, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, C6- C14 aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, C6-C14aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13; R11is H or C1-C6alkyl optionally substituted by halo; and R11and R12, independently of each other and independently at each occurrence, are H or C1-C6 alkyl optionally substituted by C1-C6 alkoxy, halo, or -OH.

[0047] In some embodiments, R1is H, C1-C6alkyl, C3-C8cycloalkyl, C6-C14aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C3- C8 cycloalkyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6alkyl, C3-C8cycloalkyl, and 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 12-membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1- C6alkyl, C5-C6cycloalkyl, and 5- to 6-membered heterocyclyl, wherein the C1-C6alkyl, C5-C6 cycloalkyl, and 5- to 6-membered heterocyclyl are each independently optionally substituted by one or more RL.

[0048] In some embodiments, R1is H.

[0049] In some embodiments, R1is C1-C6 alkyl optionally substituted by one or more RL.

[0050] In some embodiments, R1is C3-C8cycloalkyl optionally substituted by one or more RL. In some embodiments, R1is C3-C6cycloalkyl optionally substituted by one or more RL. In some embodiments, R1is C5-C6 cycloalkyl optionally substituted by one or more RL. In some embodiments, R1is cyclopentyl or cyclohexyl, which is optionally substituted by one or more RL.

[0051] In some embodiments, R1is 3- to 12-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is 3- to 10-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is 5- to 6-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, the 5- to 6- membered heterocyclyl have an annular nitrogen. [0 RL , emN , orNRL.

[0053] In some embodiments, .

[0054] In some embodiments, RLis selected from the group consisting of halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and -NR12R13, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C14aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C6-C14aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C3-C8cycloalkyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10- membered heteroaryl, and -NR12R13, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or - NR12R13. In some embodiments, RLis selected from the group consisting of C1-C6 alkyl, C5- C6cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C5-C6cycloalkyl, 5- to 6-membered heterocyclyl, and 5- to 6- membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13.

[0055] In some embodiments, RLis -OR11. In some embodiments, RLis C3-C8cycloalkyl optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis 3- to 12-membered heterocyclyl optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis 5- to 10-membered heteroaryl optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis -NR12R13.

[0056] In some embodiments, RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1- C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6alkyl substituted by -OR11or C1-C6 alkoxy.

[0057] In some embodiments, R12and R13, independently of each other and independently at each occurrence, are H or C1-C6alkyl optionally substituted by C1-C6alkoxy. In some embodiments, one of R12and R13is H and the other is C1-C6alkyl optionally substituted by C1-C6 alkoxy. In some embodiments, both R12and R13are C1-C6 alkyl.

[0058] In some embodiments, R2is H. In some embodiments, R2is halo (e.g., fluoro or chloro). In some embodiments, R2is C1-C6alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1-C6 alkoxy (e.g., methoxy). In some embodiments, R2is H, F, methyl, ethyl, or methoxy.

[0059] In some embodiments, R8is H. In some embodiments, R8is halo (e.g., fluoro or chloro). In some embodiments, R8is C1-C6 alkyl (e.g., methyl or ethyl). In some embodiments, R8is C1-C6 alkoxy (e.g., methoxy).

[0060] In some embodiments, R9is H. In some embodiments, R9is halo (e.g., fluoro or chloro). In some embodiments, R9is C1-C6alkyl (e.g., methyl or ethyl). In some embodiments, R9is C1-C6 alkoxy (e.g., methoxy).

[0061] In some embodiments, R10is H and R2, R8and R9are independently H, halo, C1-6alkyl, or C1-C6alkoxy.

[0062] In some embodiments, one of R2, R8, R9and R10is halo (e.g., fluoro or chloro) and the rest are H. In some embodiments, one of R2, R8, R9and R10is C1-C6 alkyl (e.g., methyl or ethyl) and the rest are H. In some embodiments, one of R2, R8, R9and R10is C1-C6alkoxy (e.g., methoxy) and the rest are H.

[0063] In some embodiments, R2, R8, R9and R10are H.

[0064] In some embodiments, R3, R4, R5, R6and R7are independently selected from the group consisting of H, halo, OH, C1-C6alkyl, and C1-C6alkoxy. In some embodiments, R3, R4, R5, R6and R7are independently H, fluoro, chloro, OH, methyl or methoxy. In some embodiments, R3, R4, R5, R6and R7are independently halo.

[0065] In some embodiments, R3and R4are fluoro. In some embodiments, one of R3and R4is fluoro and the other is H. In some embodiments, R3is H and R4is fluoro.

[0066] In some embodiments, R5, R6and R7are independently selected from the group consisting of H, halo, OH, C1-C6 alkyl, and C1-C6 alkoxy. In some embodiments, R5, R6and R7are independently H, fluoro, chloro, OH, methyl or methoxy.

[0067] In some embodiments, R5and R7are H and R6is halo (e.g., fluoro or chloro). In some embodiments, R5and R7are H and R6is C1-C6 alkyl (e.g., methyl or ethyl). In some embodiments, R5and R7are H and R6is C1-C6 alkoxy (e.g., methoxy).

[0068] In some embodiments, X and Y are each independently CRaRb, C=O, or O, wherein Raand Rbare each independently H, -OR11, -NR12R13, or C1-C6 alkyl.

[0069] In some embodiments, X is CRaRb, wherein Raand Rbare each independently H, - OR11, -NR12R13, or C1-C6alkyl. In some embodiments, X is CRaRb, wherein Raand Rbare each independently H, -OH, -NH2, or C1-C6 alkyl. In some embodiments, X is CH2, CH(OH), C(OH)CH3, CH(NH2), C=O, or O. In some embodiments, X is CH(OH).

[0070] In some embodiments, Y is CH2, C(CH3)2, C=O or O. In some embodiments, Y is CH2.In some embodiments, Y is O.

[0071] In some embodiments, Rcis H. In some embodiments, Rcis OH.

[0072] In some embodiments, n is 1. In some embodiments, n is 2.

[0073] In some embodiments, Rcis H, n is 1, and the moiety:R6 R7is selected from the group consisting of:H Cl ,Cl,Cl,Cl,O O O O H Cl, Cl Cl

[0074] In some embodiments, the moiety is. In some embodiments, the mIn some embodiments, the moiety ise embodiments, the moiety is C. In some embodiments, the moiety iIn some embodiments, the moiety is C.

[0075] In some embodiments, Rcis H, n is 2, and the moiety:R6R7is selected from the group consisting ofCl andCl.

[0076] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety may be combined with every description, variation,embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, any embodiments provided herein of a compound of formula (I), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, such as embodiments related to R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y, Rc, n, RL, R11, R12, and R13, apply to formulas (I-1), (I-2), (I-2), (II), (II-1), (II-2), (IIa), (IIa-1), (IIa-2), (III), (III-1), (III-2), (IIIa), or (IIIa-1), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, the same as if each and every embodiment were specifically and individually listed. It is also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, uses, articles of manufacture, or other aspects detailed herein.

[0077] In some embodiments, provided is a compound of Formula (I-1): R3R); or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Rc, n, X, and Y are as defined for formula (I).

[0078] In some embodiments, provided is a compound of Formula (I-2): R(I-2); or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, Rc, n, X, and Y are as defined for formula (I).

[0079] In some embodiments, provided is a compound of Formula (II):R3R10R8O R );or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9and R10are as defined for formula (I).

[0080] In some embodiments of the compound of the formula (II), R1is H, C1-C6alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10- membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6alkyl, C3-C8cycloalkyl, and 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 12- membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6alkyl, C5-C6cycloalkyl, and 5- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C5-C6 cycloalkyl, and 5- to 6-membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H. In some embodiments, R1is C1-C6alkyl optionally substituted by one or more RL. In some embodiments, R1is C3-C8cycloalkyl optionally substituted by one or more RL. In some embodiments, R1is cyclopentyl or cyclohexyl, which is optionally substituted by one or more RL. In some embodiments, R1is 3- to 12-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is 5- to 6-membered heterocyclyl optionally su ,NH HN HN,NH, , , , orNH. In someem , or em

[0081] In some embodiments of the compound of formula (II), RLis selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10- membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or - NR12R13. In some embodiments, RLis selected from the group consisting of C1-C6alkyl, C5- C6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and -NR12R13, wherein the C1-C6 alkyl, C5-C6 cycloalkyl, 5- to 6-membered heterocyclyl, and 5- to 6- membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis -OR11. In some embodiments, RLis C3-C6 cycloalkyl optionally substituted by -OR11. In some embodiments, RLis 5- to 6-membered heterocyclyl. In some embodiments, RLis 5- to 6-membered heteroaryl. In some embodiments, RLis -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6alkyl substituted by -OR11or C1-C6alkoxy. In some embodiments, RLis unsubstituted C1-C6alkyl.

[0082] In some embodiments of the compound of formula (II), R2is H, halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo (e.g., fluoro or chloro). In some embodiments, R2is C1-C6 alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1-C6 alkoxy (e.g., methoxy).

[0083] In some embodiments of the compound of formula (II), R3and R4are fluoro. In some embodiments, R3is H and R4is fluoro.

[0084] In some embodiments of the compound of formula (II), R5and R7are independently selected from H, hydroxy, and methoxy. In some embodiments of the compound of formula (II), R5and R7are H.

[0085] In some embodiments of the compound of formula (II), R6is selected from chloro and fluoro. In some embodiments, R6is chloro. In some embodiments, R6is fluoro.

[0086] In some embodiments of the compound of formula (II), R8is H or fluoro. In some embodiments, R8is H. In some embodiments, R9is H, fluoro, or methyl. In some embodiments, R9is H. In some embodiments, R10is H.

[0087] In some embodiments, provided is a compound of Formula (II-1): R); or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8and R9are as defined for formula (I).

[0088] In some embodiments of the compound of the formula (II-1), R1is H, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10- membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 12- membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C5-C6 cycloalkyl, and 5- to 6-memberedheterocyclyl, wherein the C1-C6 alkyl, C5-C6 cycloalkyl, and 5- to 6-membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H. In some embodiments, R1is C1-C6 alkyl optionally substituted by one or more RL. In some embodiments, R1is C3-C8 cycloalkyl optionally substituted by one or more RL. In some embodiments, R1is cyclopentyl or cyclohexyl, which is optionally substituted by one or more RL. In some embodiments, R1is 3- to 12-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is 5- to 6-membered heterocyclyl optionally su eL, or emo men s, s , or . n some em o men s, s .

[0089] In some embodiments of the compound of formula (II-1), RLis selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10- membered heteroaryl, and -NR12R13, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or - NR12R13. In some embodiments, RLis selected from the group consisting of C1-C6 alkyl, C5- C6cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C5-C6cycloalkyl, 5- to 6-membered heterocyclyl, and 5- to 6- membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis -OR11. In some embodiments, RLis C3-C6 cycloalkyl optionally substituted by -OR11. In some embodiments, RLis 5- to 6-membered heterocyclyl. In some embodiments, RLis 5- to 6-membered heteroaryl. In some embodiments, RLis -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6alkyl substituted by -OR11or C1-C6alkoxy. In some embodiments, RLis unsubstituted C1-C6alkyl.

[0090] In some embodiments of the compound of formula (II-1), R2is H, halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo (e.g., fluoro or chloro). In some embodiments, R2is C1-C6 alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1-C6 alkoxy (e.g., methoxy).

[0091] In some embodiments of the compound of formula (II-1), R3and R4are fluoro. In some embodiments, R3is H and R4is fluoro.

[0092] In some embodiments of the compound of formula (II-1), R5and R7are independently selected from H, hydroxy, and methoxy. In some embodiments of the compound of formula (II), R5and R7are H.

[0093] In some embodiments of the compound of formula (II-1), R6is selected from chloro and fluoro. In some embodiments, R6is chloro. In some embodiments, R6is fluoro.

[0094] In some embodiments of the compound of formula (II-1), R8is H or fluoro. In some embodiments, R8is H. In some embodiments, R9is H, fluoro, or methyl. In some embodiments, R9is H.

[0095] In some embodiments, provided is a compound of Formula (II-2): RR6R7(II-2);or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7and R8are as defined for formula (I).

[0096] In some embodiments of the compound of the formula (II-2), R1is H, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10- membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 12- membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C5-C6 cycloalkyl, and 5- to 6-membered heterocyclyl, wherein the C1-C6 alkyl, C5-C6 cycloalkyl, and 5- to 6-membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H. In some embodiments, R1is C1-C6alkyl optionally substituted by one or more RL. In some embodiments, R1is C3-C8 cycloalkyl optionally substituted by one or more RL. In some embodiments, R1is cyclopentyl or cyclohexyl, which is optionally substituted by one or more RL. In some embodiments, R1is 3- to 12-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is 5- to 6-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is, , emL,R HN ,NRLNH NR HN NR , , , ,NH, orN In eRLembodiments .

[0097] In some embodiments of the compound of formula (II-2), RLis selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10- membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or - NR12R13. In some embodiments, RLis selected from the group consisting of C1-C6 alkyl, C5- C6cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and -NR12R13, wherein the C1-C6 alkyl, C5-C6 cycloalkyl, 5- to 6-membered heterocyclyl, and 5- to 6- membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis -OR11. In some embodiments, RLis C3-C6cycloalkyl optionally substituted by -OR11. In some embodiments, RLis 5- to 6-membered heterocyclyl. In some embodiments, RLis 5- to 6-membered heteroaryl. In some embodiments, RLis -NR12R13. In some embodiments, RLis C1-C6alkyl optionally substituted by halo, -OR11, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6 alkyl substituted by -OR11or C1-C6 alkoxy. In some embodiments, RLis unsubstituted C1-C6 alkyl.

[0098] In some embodiments of the compound of formula (II-2), R2is H, halo, C1-C6alkyl, or C1-C6 alkoxy. In some embodiments, R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo (e.g., fluoro or chloro). In some embodiments, R2is C1-C6alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1-C6alkoxy (e.g., methoxy).

[0099] In some embodiments of the compound of formula (II-2), R3and R4are fluoro. In some embodiments, R3is H and R4is fluoro.

[0100] In some embodiments of the compound of formula (II-2), R5and R7are independently selected from H, hydroxy, and methoxy. In some embodiments of the compound of formula (II), R5and R7are H.

[0101] In some embodiments of the compound of formula (II-2), R6is selected from chloro and fluoro. In some embodiments, R6is chloro. In some embodiments, R6is fluoro.

[0102] In some embodiments of the compound of formula (II-2), R8is H or fluoro. In some embodiments, R8is H.

[0103] In some embodiments, the compound of formula (II) is of the formula (IIa): 10 8F R );or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R6, R8, R9and R10are as defined for formula (I).

[0104] In some embodiments of the compound of the formula (IIa), R1is H, C1-C6 alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10- membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6alkyl, C3-C8cycloalkyl, and 3- to 12-membered heterocyclyl, wherein the C1-C6alkyl, C3-C8cycloalkyl, and 3- to 12- membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C5-C6 cycloalkyl, and 5- to 6-membered heterocyclyl, wherein the C1-C6alkyl, C5-C6cycloalkyl, and 5- to 6-membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H. In some embodiments, R1is C1-C6 alkyl optionally substituted by one or more RL. In some embodiments, R1is C3-C8cycloalkyl optionally substituted by one or more RL. In some embodiments, R1is cyclopentyl or cyclohexyl, which is optionally substituted by one or more RL. In some embodiments, R1is 3- to 12-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is 5- to 6-membered heterocyclyl optionallysu em , orRLembodiments, R.

[0105] In some embodiments of the compound of formula (IIa), RLis selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10- membered heteroaryl, and -NR12R13, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12- membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or - NR12R13. In some embodiments, RLis selected from the group consisting of C1-C6 alkyl, C5- C6cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C5-C6cycloalkyl, 5- to 6-membered heterocyclyl, and 5- to 6- membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis -OR11. In some embodiments, RLis C3-C6cycloalkyl optionally substituted by -OR11. In some embodiments, RLis 5- to 6-membered heterocyclyl. In some embodiments, RLis 5- to 6-membered heteroaryl. In some embodiments, RLis -NR12R13. In some embodiments, RLis C1-C6alkyl optionally substituted by halo, -OR11, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6alkyl substituted by -OR11or C1-C6 alkoxy. In some embodiments, RLis unsubstituted C1-C6 alkyl.

[0106] In some embodiments of the compound of formula (IIa), R2is H, halo, C1-C6 alkyl, or C1-C6alkoxy. In some embodiments, R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo (e.g., fluoro or chloro). In some embodiments, R2is C1-C6 alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1-C6 alkoxy (e.g., methoxy).

[0107] In some embodiments of the compound of formula (IIa), R6is selected from chloro and fluoro. In some embodiments, R6is chloro. In some embodiments, R6is fluoro.

[0108] In some embodiments of the compound of formula (IIa), R8is H or fluoro. In some embodiments, R8is H. In some embodiments, R9is H, fluoro, or methyl. In some embodiments, R9is H. In some embodiments, R10is H.

[0109] In some embodiments, the compound of formula (II) is of formula (IIa-1) or formula (IIa-2): R1r R1( a- ).

[0110] In some embodiments of the compound of the formula (IIa-1) or (IIa-2), R1is H, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6alkyl, C3-C8cycloalkyl, and 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 12-membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H, C1-C6 alkyl, C5-C6 cycloalkyl, and 5- to 6- membered heterocyclyl, wherein the C1-C6 alkyl, C5-C6 cycloalkyl, and 5- to 6-membered heterocyclyl are each independently optionally substituted by one or more RL. In some embodiments, R1is H. In some embodiments, R1is C1-C6alkyl optionally substituted by one or more RL. In some embodiments, R1is C3-C8 cycloalkyl optionally substituted by one or more RL. In some embodiments, R1is cyclopentyl or cyclohexyl, which is optionally substituted by one or more RL. In some embodiments, R1is 3- to 12-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is 5- to 6-membered heterocyclyl optionally substituted by one or more RL. In some embodiments, R1is RL, O , or ts, 1R is .

[0111] In some embodiments of the compound of formula (IIa-1) or (IIa-2), RLis selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12- membered heterocyclyl, or -NR12R13. In some embodiments, RLis selected from the groupconsisting of C1-C6 alkyl, C5-C6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6- membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C5-C6cycloalkyl, 5- to 6- membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or - NR12R13. In some embodiments, RLis -OR11. In some embodiments, RLis C3-C6cycloalkyl optionally substituted by -OR11. In some embodiments, RLis 5- to 6-membered heterocyclyl. In some embodiments, RLis 5- to 6-membered heteroaryl. In some embodiments, RLis - NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1- C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6alkyl substituted by -OR11or C1-C6 alkoxy. In some embodiments, RLis unsubstituted C1-C6 alkyl.

[0112] In some embodiments of the compound of formula (IIa-1) or (IIa-2), R2is H, halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo (e.g., fluoro or chloro). In some embodiments, R2is C1-C6alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1- C6alkoxy (e.g., methoxy).

[0113] In some embodiments of the compound of formula (IIa-1) or (IIa-2), R6is selected from chloro and fluoro. In some embodiments, R6is chloro. In some embodiments, R6is fluoro.

[0114] In some embodiments of the compound of formula (IIa-1) or (IIa-2), R8is H or fluoro. In some embodiments, R8is H. In some embodiments, R9is H, fluoro, or methyl. In some embodiments, R9is H. In some embodiments, R10is H.

[0115] In some embodiments, provided is a compound of Formula (III): RR6R7(III);or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RL, R2, R3, R4, R5, R6, R7, R8, R9and R10, as well as X and Y are as defined for formula (I).

[0116] In some embodiments of the compound of the formula (III), RLis selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1-C6 alkoxy, or -NR12R13. In some embodiments, RLis C1-C6alkyl optionally substituted by C1-C6alkoxy.

[0117] In some embodiments of the compound of the formula (III), R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo. In some embodiments, R2is C1-C6alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1- C6 alkoxy (e.g., methoxy).

[0118] In some embodiments of the compound of the formula (III), R6is halo. In some embodiments, R6is chloro.

[0119] In some embodiments of the compound of the formula (III), R8is H or halo. In some embodiments, R8is H or fluoro. In some embodiments, R8is H.

[0120] In some embodiments, provided is a compound of Formula (III-1): R(III-1); or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RL, R2, R3, R4, R5, R6, R7, R8and R9, as well as X and Y are as defined for formula (I).

[0121] In some embodiments of the compound of the formula (III-1), RLis selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-memberedheterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1-C6 alkoxy, or -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by C1-C6 alkoxy.

[0122] In some embodiments of the compound of the formula (III-1), R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo. In some embodiments, R2is C1-C6 alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1- C6 alkoxy (e.g., methoxy).

[0123] In some embodiments of the compound of the formula (III-1), R6is halo. In some embodiments, R6is chloro.

[0124] In some embodiments of the compound of the formula (III-1), R8is H or halo. In some embodiments, R8is H or fluoro. In some embodiments, R8is H.

[0125] In some embodiments, provided is a compound of Formula (III-2): R); or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RL, R2, R3, R4, R5, R6, R7and R8, as well as X and Y are as defined for formula (I).

[0126] In some embodiments of the compound of the formula (III-2), RLis selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1-C6 alkoxy, or -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by C1-C6 alkoxy.

[0127] In some embodiments of the compound of the formula (III-2), R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo. In some embodiments, R2is C1-C6 alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1- C6 alkoxy (e.g., methoxy).

[0128] In some embodiments of the compound of the formula (III-2), R6is halo. In some embodiments, R6is chloro.

[0129] In some embodiments of the compound of the formula (III-2), R8is H or halo. In some embodiments, R8is H or fluoro. In some embodiments, R8is H.

[0130] In some embodiments, the compound of formula (III) is of the formula (IIIa): F R X(IIIa); or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RL, R2, R6, R8, R9and R10, as well as X and Y are as defined for formula (I).

[0131] In some embodiments of the compound of the formula (IIIa), RLis selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1-C6 alkoxy, or -NR12R13. In some embodiments, RLis C1-C6 alkyl optionally substituted by C1-C6 alkoxy.

[0132] In some embodiments of the compound of the formula (IIIa), R2is H, F, methyl, ethyl, or methoxy. In some embodiments, R2is H. In some embodiments, R2is halo. In some embodiments, R2is C1-C6 alkyl (e.g., methyl or ethyl). In some embodiments, R2is C1- C6alkoxy (e.g., methoxy).

[0133] In some embodiments of the compound of the formula (IIIa), R6is halo. In some embodiments, R6is chloro.

[0134] In some embodiments of the compound of the formula (IIIa), R8is H or halo. In some embodiments, R8is H or fluoro. In some embodiments, R8is H.

[0135] In some embodiments of the compound of the formula (IIIa), R10is H. In some embodiments, R9and R10are H.

[0136] In some embodiments of the compound of the formula (IIIa), X is CH2,CH(OH), C(OH)CH3, C=O, or O. In some embodiments, X is CH(OH). In some embodiments, Y is CRaRbor O, wherein Raand Rbare each independently H or C1-C6 alkyl. In some embodiments, Y is O, CH2, or C(CH3)2. In some embodiments, Y is O or CH2.

[0137] In some embodiments, the compound of formula (IIIa) is of formula (IIIa-1): F R).

[0138] In some embodiments of the compound of the formula (IIIa-1), RLis C1-C6 alkyl optionally substituted by halo, -OR11, C1-C6 alkoxy, or -NR12R13. In some embodiments, RLis C1-C6alkyl optionally substituted by C1-C6alkoxy. In some embodiments, Y is CRaRbor O, wherein Raand Rbare each independently H or C1-C6alkyl. In some embodiments, Y is O, CH2, or C(CH3)2. In some embodiments, Y is O or CH2. In some embodiments, R6is halo. In some embodiments, R6is chloro.

[0139] The compound can be selected from any one of exemplary compounds as shown in Table 1, a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from compounds 1-74 of Table 1. Representative compounds are listed in Table 1. Table 1No. Structure 1 2 3 4 5No. Structure 6 7 8 9 1No. Structure 1 1 1 1 1No. Structure 1 1 1No. Structure 1 2 2 2 2No. Structure 2 2 2 2 2No. Structure 2 3 3 3 3No. Structure 3 3 3 3 3No. Structure 3 4 4 4 4No. Structure 4 4 4 4 4No. Structure 4 5 5 5No. Structure 5 5 5 5No. Structure 5 5 5 6No. Structure 6 6 6 6No. Structure 6 6 6 6No. Structure 6 7 7 7No. Structure 7 7 7 7No. Structure 7 7 7 8 8No. Structure 8 8 8 H 8 8No. Structure 8 H 8 8 9 9No. Structure 9 9 9 9 9 9No. Structure 9 9 1 1 1No. Structure 1 1 1 1 1No. Structure 1 1 1 1 1No. Structure 1 1 1 1 1 1No. Structure 1 1 1 1or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, provided herein is a compound described in Table 1, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and uses thereof. In some embodiments, provided herein is a compound described in Table 1, or a pharmaceutically acceptable salt thereof.

[0141] Provided herein is a compound selected from the group consisting of: 6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((1-(pyridin-2-yl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((1-(pyridin-3-yl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((1-(pyridin-4-yl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(pyridin-2-yl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(pyridin-3-yl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(pyridin-4-yl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxypropyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxycyclopentyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(1-methoxypropan-2-yl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(tetrahydrofuran-3-yl)piperidin-4-yl)amino)quinazolin- 6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-propylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3- ((methylamino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(3-(2-((3-(dimethylamino)propyl)amino)-8-methoxyquinazolin-6-yl)-2,4- difluorophenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(3-(2-((2-(dimethylamino)ethyl)amino)-8-methoxyquinazolin-6-yl)-2,4- difluorophenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-1-methyl-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-oxo-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide-1-d;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3-(((2- methoxyethyl)(methyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((1-methylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-2,3-dihydrobenzofuran-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3-(((2- methoxyethyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((1-(2-methoxyethyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxy-2-methylpropyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)benzo[d][1,3]dioxole-4-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-2,3-dihydrobenzofuran-7-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)- 1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-3-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-isopropylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)quinazolin- 6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(3-(2-((1-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;N-(3-(8-ethyl-2-((4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; N-(2,4-difluoro-3-(2-((4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-6- fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; N-(2,4-difluoro-3-(2-((1-methylpiperidin-3-yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 1-amino-N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-2,3-dihydro-1H- indene-4-sulfonamide; N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; N-(2,4-difluoro-3-(2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-6-fluoro-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(3-(8-ethyl-2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 3-chloro-N-(3-(8-ethyl-2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1,5-dihydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1,7-dihydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-1-hydroxy- 5-methoxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-1-hydroxy- 7-methoxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1,2-dihydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 3-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-3,3-dimethyl-2,3-dihydro-1H-indene-4-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((4-((2- methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-4-hydroxychromane-8-sulfonamide; N-(3-(2-((4-aminocyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; N-(3-(2-((4-(bis(2-methoxyethyl)amino)cyclohexyl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6- yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((4-morpholinocyclohexyl)amino)quinazolin-6-yl)phenyl)- 1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(3,3,3-trifluoropropyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-(pyridin-4-ylamino)quinazolin-6-yl)phenyl)-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-(trifluoromethoxy)ethyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide. 6-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((1-methylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((1-(2-methoxyethyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((1-methylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 5-chloro-N-(3-(8-ethyl-2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((1-methylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((1-methylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((1-ethylpiperidin-4-yl)amino)-5-fluoroquinazolin-6-yl)-2,4- difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((1-(2-methoxyethyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((1-isopropylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(3-(8-ethyl-2-((1-isopropylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(3-(2-((1-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3- hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(3-(8-ethyl-2-((1-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4- difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(3-(8-ethyl-2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)- 2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((1-methylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(3-(2-((1-ethylpiperidin-4-yl)amino)-8-fluoroquinazolin-6-yl)-2,4- difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((1-isopropylpiperidin-4-yl)amino)quinazolin-6- yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((1-(2-methoxyethyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; 5-chloro-N-(3-(2-((1-cyclopropylpiperidin-4-yl)amino)-5-fluoroquinazolin-6-yl)-2,4- difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; N-(3-(2-((4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-5- chloro-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide; N-(3-(2-amino-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-3-hydroxy-2,3- dihydrobenzofuran-7-sulfonamide; N-(3-(2-amino-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide; N-(3-(2-amino-8-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-3-hydroxy-2,3- dihydrobenzofuran-7-sulfonamide;N-(3-(2-amino-8-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(7-fluoro-2-((1-(2-methoxyethyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)-7- methylquinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; N-[3-(2-amino-5-fluoroquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-3-hydroxy-2,3- dihydro-1-benzofuran-7-sulfonamide; 5-chloro-N-(3-{8-ethyl-5-fluoro-2-[(1-methylpiperidin-4-yl) amino] quinazolin-6-yl}- 2,4-difluorophenyl)-3-hydroxy-2,3-dihydro-1-benzofuran-7-sulfonamide; N-[3-(2-amino-5-fluoroquinazolin-6-yl)-2,4-difluorophenyl]-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide; 6-chloro-N-[2,4-difluoro-3-(2-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-7- methylquinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; formic acid; 6-chloro-N-[2,4-difluoro-3-(7-fluoro-2-{[1-(2-methoxyethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(2-fluoro-3-{2-[(1-methylpiperidin-4-yl) amino] quinazolin-6-yl} phenyl)-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-(4-fluoro-3-(2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 6-chloro-N-{2,4-difluoro-3-[2-(oxan-4-ylamino) quinazolin-6-yl]phenyl}-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide; 5-chloro-N-{3-[8-ethyl-2-(piperidin-4-ylamino) quinazolin-6-yl]-2,4-difluorophenyl}-3- hydroxy-2,3-dihydro-1-benzofuran-7-sulfonamide; 5-chloro-N-(3-{8-ethyl-2-[(1-ethylpiperidin-4-yl)amino]quinazolin-6-yl}-2- fluorophenyl)-3-hydroxy-2,3-dihydro-1-benzofuran-7-sulfonamide; 5-chloro-N-[2-fluoro-3-(5-fluoro-2-{[1-(2-methoxyethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-3-hydroxy-2,3-dihydro-1-benzofuran-7-sulfonamide; 5-chloro-N-(2-fluoro-3-{5-fluoro-2-[(1-methylpiperidin-4-yl)amino]quinazolin-6- yl}phenyl)-3-hydroxy-2,3-dihydro-1-benzofuran-7-sulfonamide; 5-chloro-N-{3-[8-ethyl-2-(oxan-4-ylamino) quinazolin-6-yl]-2,4-difluorophenyl}-3- hydroxy-2,3-dihydro-1-benzofuran-7-sulfonamide; and5-chloro-N-{2,4-difluoro-3-[5-fluoro-2-(piperidin-4-ylamino) quinazolin-6-yl] phenyl}- 3-hydroxy-2,3-dihydro-1-benzofuran-7-sulfonamide. or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

[0142] Also provided herein are, where applicable, any and all stereoisomers of the compounds depicted herein, including geometric isomers (e.g., cis / trans isomers or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio, including racemic mixtures.

[0143] The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.

[0144] The present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described, such as the compounds of Table 1. The structure or name is intended to embrace all possible stereoisomers of a compound depicted. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or nonracemic mixture.

[0145] The invention also intends isotopically-labeled and / or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as2H,3H,11C,13C,14C13N,15O,17O,32P,35S,18F,36Cl. Certain isotope labeled compounds (e.g.3H and14C) is useful in compound or substratetissue distribution studies. Incorporation of heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.

[0146] Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically- labeled reagents in place of the corresponding non-labeled reagent.

[0147] Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.

[0148] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration.

[0149] One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.

[0150] The compounds of the invention may be prepared by a number of processes as generally described below. In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

[0151] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance LiquidChromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

[0152] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

[0153] For GCN2 enzyme assays, testing compounds were prepared at proper concentrations in DMSO solution. IC50 values were calculated from a remaining activity using read conversion ratio. Pharmaceutical Compositions and Formulations

[0154] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Accordingly, in some embodiments of the invention, there is provided a pharmaceutical composition comprising at least one compound of Formula (I) as defined above together with at least one pharmaceutically acceptable excipient.

[0155] The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, buffering agents, tonicity- adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.

[0156] The term “pharmaceutically acceptable” as used herein means compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0157] Pharmaceutical compositions containing compounds of the Formula (I) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions can be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.

[0158] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0159] The composition may be a tablet composition or a capsule composition. Tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0160] Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the GI tract.

[0161] The pharmaceutical compositions typically comprise from approximately 1% (w / w) to approximately 95%, preferably% (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients. Preferably, the compositions comprise from approximately 20% (w / w) to approximately 90% (w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically excipient or combination of excipients. The pharmaceutical compositionscomprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragées, powders, tablets or capsules.

[0162] Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers / or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would in addition typically contain 0-99% (w / w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0163] The composition may be a parenteral composition. Parenteral formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-99% (w / w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w / w) oils.

[0164] The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack.

[0165] The compounds of the Formula (1) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g., from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g., 0.1 milligrams to 2 milligrams of active ingredient).

[0166] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g., 100 milligrams to 1 gram, of active compound.

[0167] The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeuticeffect (effective amount). The precise amounts of compound administered may be determined by a supervising physician in accordance with standard procedures. Methods of Use and Uses

[0168] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and / or for conducting quality control assays.

[0169] Provided herein is a method of treating a disease or disorder in an individual in need thereof comprising administering a compound describes herein or any embodiment, variation, or aspect thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound, pharmaceutically acceptable salt thereof, or composition is administered to the individual according to a dosage and / or method of administration described herein.

[0170] Further embodiments of the invention include the use of a compound of Formula (I) or a salt thereof or a pharmaceutical composition comprising a compound of Formula (I) as a GCN2 modulator. Compounds of the present invention may be used as GCN2 modulators. Compounds of the present invention may be used as GCN2 inhibitors, antagonists or agonists. Compounds of the present invention may be used in the treatment of a disease or disorder characterised by activation of GCN2.

[0171] Compounds of the present invention may be used in the treatment of cancer, neurodegenerative diseases, chronic infections or conditions or symptoms related thereto.

[0172] Compounds of the present invention may be used in the treatment of cancer. In some embodiments, compounds of the present invention are used to treat breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, cancer of secretory cells, myelodysplastic syndrome,myeloproliferative neoplasm, malignant glioma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia. small cell lung cancer, malignant pleural mesothelioma, Head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma, pediatric neuroblastoma or conditions or symptoms related thereto.

[0173] In some embodiments, compounds and compositions detailed herein are used as modulators of GCN2. Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a compound of Formula (I) or any embodiment, variation or aspect thereof.

[0174] It was demonstrated that GCN2 may be used as an immune regulator. GCN2 senses tryptophan and L-arginine deficiency. Indoleamine 2,3-dioxygenase (IDO) is a potent immunoregulatory enzyme that mediates conversion of the essential amino acid tryptophan (Trp) to kyneurines and its expression allows certain macrophages and dendritic cells (DCs) to inhibit T cell proliferation (Grohmann et al., 2003, Mellor and Munn, 2004). IDO and the subsequent tryptophan starvation triggers a GCN2-dependent stress signalling pathway that induced profound anergy in responding T cells. GCN2-knockout cells are refractory to IDO- induced cell cycle arrest and anergy. IDO-expressing plasmacytoid DCs are found in tumor- draining lymph nodes and activates the GCN2 kinase pathway in responding T cells. T cells with a targeted disruption of GCN2 are not susceptible to IDO-mediated suppression of proliferation. (Munn et al., 2005). GCN2 activation through accumulation of unloaded tRNAs leads to inhibition of CD8+ effector T-cells and increase in generation and activation of regulatory T-cells.

[0175] IFN-γ is a cytokine that is produced mostly by activated T cells and NK cells and has complex effects on immune and nonimmune cells. IFN-γ plays important roles in inflammation, making it particularly relevant to transplantation and autoimmune diseases. IFN-γ induces Trp metabolism, which then activates GCN2 kinase, leading to the phosphorylation of the eIF2α, an activator of autophagy. Conversely, Trp supplementation reduces the activation of the GCN2–eIF2α pathway and inhibits autophagy Further targetingof GCN2 expression by RNA interference also inhibits IFN-γ–induced autophagy (Fougeray et al., 2012).

[0176] GCN2 plays a central role in regulating the cell-cycle arrest induced by L- Arginine (L-Arg) starvation. L-Arg is a nonessential amino acid that plays a central role in regulating the immune response (Bronte and Zanovello, 2005). In tumor-infiltrating myeloid cells, L-Arg is converted by arginase I and arginase II to urea and ornithine and oxidized by the inducible form of nitric oxide synthase to citrulline and nitric oxide. Thus, L-Arg is profoundly reduced in cancer patients, following liver transplantation, or in severe trauma by an increased production of arginase I (Zea et al., 2005; Roth et al., 1994; Angele et al., 1999). Increased arginase activity is frequently observed in patients with breast, prostate, lung and colon cancer (Cederbaum et al., 2004). This results in a decreased T-cell proliferation and an impaired T-cell function. GCN2-knockout T cells did not show a decreased proliferation in the absence of L-Arg (Rodriguez et al., 2006).

[0177] GCN2 activation via L-Arg deprivation was also shown to occur in astrocytes, similar to how activation of GCN2 kinase mediates proliferative arrest and T-cell anergy induction in response to Trp deprivation by IDO. L-Arg consumption by arginase 1 in tumor- conditioned ges mediated GCN2 kinase-dependent cell cycle arrest in the G0-G1 phase and downregulation of the ζ chain of the TCR / CD3 complex in antigen-activated T cells (Rodriguez et al., 2002).

[0178] Activation of GCN2 through amino acid deficient-conditions promotes macrophage inflammation and mortality in a mouse model of septicemia. GCN2 knockout macrophages had a significant reduction of cytokine gene expression after lipopolysaccharide (LPS) stimulation. When monocytic-lineage-specific GCN2 knockout mice were challenged with a lethal dose of LPS, mice showed reduced inflammatory responses, with decreased IL-6 and IL-12 expression correlating with significant reduction in animal mortality (Liu et al., 2014).

[0179] In some embodiments, provided herein is a method of treating a disease mediated by the GCN2 pathway in an individual comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the individual.

[0180] In some embodiments, provided herein is a method of treating a disease characterised by activation of the GCN2 pathway in an individual comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the individual.

[0181] In some embodiments, provided herein is a method of treating a disease in an individual, wherein the individual has a low level of an amino acid. In some embodiments, the individual has a low level of a nonessential amino acid. In some embodiments, the individual has a low level of L-arginine. In some embodiments, the individual has a low level of L-tryptophan. In some embodiments, the disease results in a low level of L-arginine in a specific tissue or cell type, such as a tumor or an immune cell. In some embodiments, the disease results in a low level of L-tryptophan in a specific tissue or cell type, such as a tumor or an immune cell. In some embodiments, the level of L-tryptophan is less than 200 µM, less than 100 µM, less than 75 µM, less than 50 µM, or less than 25 µM. In some embodiments, the level of L-tryptophan is 10 µM to 75 µM. In some embodiments, the level of L-arginine is less than 200 µM, less than 100 µM, less than 75 µM, less than 50 µM, or less than 25 µM. In some embodiments, the level of L-arginine is 10 µM to 75 µM.

[0182] Also provided herein is a method of treating a disease in an individual, wherein the disease involves overexpression of GCN2. In some embodiments, provided herein is a method of treating a disease in an individual, wherein the disease involves activation of GCN2. In some embodiments, GCN2 is overexpressed and / or activated in a in specific tissue or cell type, such as a tumor or an immune cell.

[0183] In some embodiments, the methods provided herein inhibit a stress response in a cell. In some embodiments, the stress response is involved protecting cancer cells. In some embodiments, the stress response relates to amino acid starvation. In some embodiments, the stress response is a the unfolded protein response. In some embodiments, the stress response is an ER stress response.

[0184] In some embodiments, the methods provided herein result in reduced phosphorylation of GCN2. In some embodiments, downstream signalling by GCN2 is reduced. In some embodiments, phosphorylation of eIF2a kinase is reduced.

[0185] It was described that persistent parasite or viral infections are associated to the local induction of IDO expression affecting the activation of a proper immune response. It was also demonstrated that cutaneous Leishmania major infection stimulated expression of IDO in local lymph nodes. Induced IDO attenuated the T cell stimulatory functions of dendritic cells and suppressed local T cell responses to exogenous and nominal parasite antigens (Makala et al., 2011).

[0186] It was also demonstrated the role of IDO in leprosy. An increased number of macrophages / dendritic cells expressing IDO were found in lepromatous compared to reversal reaction patients. Furthermore, an increased IDO message in Mycobacterium leprae- stimulated peripheral blood mononuclear cells were also found. These data suggest that M. leprae chronic infection activates the suppressive molecule IDO which, in turn, contributes to the specific immunosuppression observed in lepromatous leprosy (de Souza et al., 2011).

[0187] It was described that HIV inhibits CD4+ T-cell proliferation by inducing IDO in plasmacytoid dendritic cells and that in vitro inhibition of IDO results in increased CD4(+) T- cell proliferative response in peripheral blood mononuclear cells from HIV-infected patients (Boasso et al., 2007).

[0188] Accordingly, inhibitors of the IDO / GCN2 pathway as disclosed herein could be used to enhance immune responses to chronic and persistent infections. In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating or preventing a viral infection. In some embodiments, the viral infection is an African swine fever virus, a dengue virus, an enterovirus, a hepatitis B virus, a hepatitis C virus, influenza virus, a tick-borne encephalitis virus, or a West Nile virus infection. In some embodiments, the viral infection is caused by a virus that activates GCN2 in an infected cell.

[0189] The basic mechanism of nutritional stress management mediated by GCN2 pathway functions primarily to couple cell growth to amino acid availability (Zhang et al., 2002).

[0190] In the tumor microenvironment, the abnormal development of vasculature results in insufficient blood supply and deprivation of glucose and amino acids. Both amino acid and glucose deprivation, stresses found in solid tumors, activated GCN2 to upregulate ATF4target genes involved in amino acid synthesis and transport. GCN2 activation / overexpression and increased phospho-eIF2α were observed in human and mouse tumors compared with normal tissues and abrogation of ATF4 or GCN2 expression significantly inhibited tumor growth in vivo (Ye et al., 2010).

[0191] ATF4 is necessary for tumor cells to maintain homeostasis of amino acid metabolism and that activation of GCN2-ATF4-asparagine synthetase (ASNS) pathway promotes tumor cell survival under nutrient (amino acid or glucose) deprivation. GCN2- eIF2α pathway is activated in various human and mouse tumor tissues. Deficiency of ATF4 or GCN2 severely inhibits tumor growth in vivo. Together, these results suggest that GCN2- ATF4-ASNS pathway is a promising target for tumor therapy.

[0192] Tumor xenograft studies of head and neck squamous cell carcinoma (HNSCC), or fibrosarcoma (HT1080) cell lines with GCN2 deletions prevented tumor growth and survival (Ye et al., 2010; Wang et al., 2013). Additionally, in response to vemurafenib, BRAF- mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism through activation of GCN2. The vemurafenib-triggered ISR, an event independent of downstream MEK inhibition, was specifically prevented by silencing GCN2, but not other eIF2α kinases. Interestingly, ATF4 silencing by siRNA rendered BRAF- mutated melanoma cells sensitive to vemurafenib. Thus, the GCN2-mediated ISR can promote cellular adaptation to vemurafenib-induced stress, providing an insight into the development of drug resistance (Nagasawa et al., 2017).

[0193] It was reported that amino acid deficiency, glucose deprivation and hypoxia promote tumor growth and angiogenesis through the GCN2 / eIF2α / ATF4 pathway (Wang et al., 2013). GCN2 expression is elevated in human tumors to overcome the stress associated to amino acid deprivation by stimulating vascular endothelial growth factor (VEGF)–mediated angiogenesis.

[0194] Leukemia cells lack the ability to synthesize asparagine. Thus, asparaginase, which functions by depletion of asparagine and glutamine, is a first line of treatment for B- Cell-derived acute lymphoblastic leukemia (B-ALL) (Terwilliger et al., 2017). It has been demonstrated that treatment with asparaginase activates GCN2 pathway in several leukemia cells and this is a mechanism by which tumor cells cope with nutrient stress by reversing chemotherapeutic amino acid deprivation (Lough et al., 2018). The inhibition of GCN2sensitizes cancer cells with low basal-level expression of asparagine synthetase (ASNS) to the anti-leukemic agent asparaginase (Nakamura et al., 2018). Thus, GCN2 inhibitors could be exploited as a single agent therapy or in combination with asparaginase.

[0195] Without being bound to any particular theory, the GCN2-eIF2α-ATF4 pathway is important for maintaining metabolic homeostasis in tumor cells, making it a novel and attractive target for anti-tumor approaches.

[0196] Compounds as GCN2 modulators as disclosed herein can be useful as a prophylactic or therapeutic agent for many GCN2 associated diseases such as cancer: colorectal cancer, gastrointestinal stromal tumor, lung cancer (e.g. small and non-small cell lung cancer, malignant mesothelioma, primary lung cancer), hematologic cancer (e.g. multiple myeloma, leukemia (e.g. acute myeloid leukemia, acute lymphocytic leukemia, chronic leukemia), malignant lymphoma, Hodgkin’s disease, non-Hodgkin’s leukemia, chronic myeloproliferative disease), cancer metastasis, precancerous lesions (e.g. bone marrow myelodysplastic syndrome), pancreatic cancer (e.g. pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophagus cancer, gastric cancer (e.g. papillary adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, breast cancer (e.g. ductal carcinoma in situ, inflammatory breast cancer, invasive ductal carcinoma), ovarian cancer (e.g. ovarian epithelial carcinoma, ovarian germ cell tumor), testis tumor, prostate cancer (e.g. hormone and non-hormone dependent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g. hepatoma, primary liver cancer), extrahepatic bile duct cancer, thyroid cancer, renal cancer (e.g. renal cell carcinoma, clear cell renal carcinoma), uterine cancer (e.g. cervix cancer, uterine body cancer, uterus sarcoma), brain tumor (e.g. glioma, glioblastoma, medulloblastoma, astrocytoma, hypophyseal adenoma), retinoblastoma, skin cancer (e.g. melanoma, basal cell carcinoma), sarcoma (e.g. rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, osteosarcoma, spindle cell sarcoma), malignant bone tumor, urinary bladder cancer. In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating cancer, such as breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, or adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma,cancer of secretory cells, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia. small cell lung cancer, malignant pleural mesothelioma, Head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma or pediatric neuroblastoma. In some embodiments, the compound, salt, or composition may be used in a method of treating metastatic kidney cancer, chronic lymphocytary leukemia, pancreatic adenocarcinoma, or non-small cell lung cancer.

[0197] The GCN2 modulation provides the opportunity for interfering with the tumor growth metabolism at the same time what may enhance the efficacy of a monotherapy or a combination therapy with other anticancer agents. In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in treating tumor in combination with other anticancer agents such as an anti-neoplastic agent, an immune checkpoint inhibitor, or any other suitable anti-cancer agent. Exemplary immune checkpoint inhibitors include anti-PD-1, anti-PD-L1, anti GITR, anti-OX-40, anti-LAG3, anti-TIM-3, anti-41BB, anti-CTLA-4 antibodies. Exemplary anti-neoplastic agents can include, for example, anti-microtubule agents, platinum coordination complexes, alkylating agents, topoisomerase II inhibitors, topoisomerase I inhibitors, antimetabolites, antibiotic agents, hormones and hormonal analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. Other anti-cancer agents can include one or more of an immuno-stimulant, an antibody or fragment thereof (e.g. an anti-CD20, anti-HER2, anti-CD52, or anti-VEGF antibody or fragment thereof), or an immunotoxin (e.g. an anti-CD33 antibody or fragment thereof, an anti-CD22 antibody or fragment thereof, a calicheamicin conjugate, or a pseudomonas exotoxin conjugate).

[0198] In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating cancer in an individual, wherein one or more cancer cells in the individual are dormant cancer cells. In some embodiments, one or more of the dormant cancer cells are disseminated tumor cells orcirculating tumor cells. In some embodiments, one or more of the dormant cancer cells are disseminated tumor cells.

[0199] In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating cancer in an individual, wherein the individual has had a prior treatment. In some embodiments, the cancer is resistant or refractory to the prior treatment. In some embodiments, the cancer has progressed on the prior treatment. In the embodiments, the cancer is a recurrent cancer. In some embodiments, the prior treatment was treatment with a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based antineoplastic drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g. doxorubicin), a pyrimidine analog (e.g.5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), an mTOR inhibitor (e.g., rapamycin), an immune-check point inhibitor, or an agent that is used in immune oncology. In some embodiments, the cancer is resistant to treatment with a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based antineoplastic drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g. doxorubicin), a pyrimidine analog (e.g.5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), an mTOR inhibitor (e.g., rapamycin), an immune-check point inhibitor, or an agent that is used in immune oncology. In some embodiments, the cancer is resistant to treatment with doxorubicin and / or rapamycin.

[0200] In some embodiments, the administration of the compound, salt, or composition reduces tumor growth, tumor proliferation, or tumorigenicity in the individual. In some embodiments, the compound, salt, or composition may be used in a method of reducing tumor growth, tumor proliferation, or tumorigenicity in an individual in need thereof. In some embodiments, tumor growth is slowed or arrested. In some embodiments, tumor growth is reduced at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the tumor is reduced in size. In some embodiments, tumor size is reduced at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, tumor metastasis is prevented or slowed. In some embodiments, the tumor growth, tumor proliferation, or tumorigenicity is compared to the tumor growth, tumor proliferation, or tumorigenicity in the individual prior to the administration of the compound, salt, or composition. In some embodiments, the tumor growth, tumor proliferation, or tumorigenicityis compared to the tumor growth, tumor proliferation, or tumorigenicity in a similar individual or group of individuals. Methods of measuring tumor growth, tumor proliferation, and tumorigenicity are known in the art, for example by repeated imaging of the individual.

[0201] In some embodiments, the administration of the compound, salt, or composition induces apoptosis of cancer cells. In some embodiments, apoptosis of cancer cells is increased at least 10%, at least 20%, at least 30%, at least 40% or at least 50% upon administration.

[0202] In some embodiments, the administration of the compound, salt, or composition reduces CHOP induction. In some embodiments, CHOP induction is reduced at least 10%, at least 20%, at least 30%, at least 40% or at least 50% upon administration.

[0203] In some embodiments, the administration of the compound, salt, or composition decreases the activity of PERK.

[0204] It was recently demonstrated that hepatic GCN2 is activated in fatty livers, and GCN2 deficiency protects against high-fat diet (HFD)-induced hepatic steatosis and insulin resistance, indicating that the role of GCN2 in lipid metabolism regulation is context dependent.

[0205] After high fat diet (HFD) feeding for 12 weeks, Gcn2- / - mice were less obese than wild-type (WT) mice, and Gcn2- / - significantly attenuated HFD-induced liver dysfunction, hepatic steatosis and insulin resistance. In the livers of the HFD-fed mice, GCN2 deficiency resulted in higher levels of lipolysis genes, lower expression of genes related to fatty acid synthesis, transport and lipogenesis, and less induction of oxidative stress. In this work it was also reported that knockdown of GCN2 attenuated, whereas overexpression of GCN2 exacerbated, palmitic acid-induced steatosis, oxidative & ER stress, and changes of peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase and metallothionein expression in HepG2 cells (Liu et al., 2018). These findings suggest that strategies to inhibit GCN2 activity in the liver may provide a novel approach to attenuate Nonalcoholic fatty liver disease (NAFLD) development.

[0206] When mice are reared with a medium fat (22 kcal% fat) diet during perinatal development, GCN2 deficiency reduced hepatic triglyceride storage (Xu et al., 2013).

[0207] It was reported that GCN2 deficiency attenuated cardiac dysfunction and hyperlipidemia in both type 1 diabetes (T1D) and Type 2 diabetes (T2D) mice, and the improved cardiac function in diabetic GCN2- / - mice was associated with reduced hypertrophy, fibrosis, lipid accumulation, oxidative stress, inflammation and apoptosis. The pathological role of GCN2 in diabetic cardiomyopathy (DCM) was also validated in high glucose or palmitic acid treated H9C2 rat cardio-myoblast cell line (Feng et al., 2019).

[0208] GCN2 deficiency attenuated transverse aortic constriction (TAC)-induced cardiac dysfunction and cardiomyocyte apoptosis by decreasing cardiomyocyte apoptosis and myocardial oxidative stress. GCN2 activation impairs adaptative responses to congestive heart failure (Lu et al., 2014). After doxorubicin-induced cardiac dysfunction, Gcn2- / - mice developed less contractile dysfunction, myocardial fibrosis, apoptosis, and oxidative stress compared with WT mice. In the hearts of the Dox-treated mice, GCN2 deficiency attenuated eIF2α phosphorylation and induction of its downstream targets, activating transcription factor 4 (ATF4) and C / EBP homologous protein (CHOP), and preserved the expression of anti- apoptotic factor Bcl-2 and mitochondrial uncoupling protein-2(UCP2) (Wang et al., 2018). These data suggest that strategies to inhibit GCN2 activity in cardiomyocyte may provide a novel approach to attenuate Dox-related cardiotoxicity.

[0209] Accordingly, in some embodiments, a compound or salt thereof described herein or a composition described herein may be used in treating or preventing metabolic and cardiac diseases.

[0210] It was demonstrated that GCN2 deletion attenuates denervation-induced muscle atrophy. GCN2 deficiency also significantly attenuated the muscle mass loss in atrophied gastrocnemius and extensor digitorum longus muscles. Similar results were observed on day 14 after denervation. Wheat germ agglutinin staining of muscle cryosections demonstrated that GCN2-deficient TA muscles had a better preservation of myofiber size in response to denervation (Guo et al., 2018). Furthermore, the detrimental effect of GCN2 in denervation- induced muscle atrophy was related to FoxO3a activation, which upregulates genes involved in both the ubiquitin-proteasome pathway and autophagy in muscle atrophy (Sandri et al., 2004; Bertaggia et al., 2012; Wei et al., 2013; Guo et al., 2016).

[0211] Accordingly, in some embodiments, a compound or salt thereof described herein or a composition described herein may be used in treating or preventing muscle atrophy.

[0212] Expression of long-lasting synaptic plasticity and long-term memory (LTM) requires protein synthesis, which can be repressed by phosphorylation of eIF2α. In mice lacking the eIF2α kinase, GCN2, the reduction in phosphorylated eIF2α is associated with altered synaptic plasticity and memory. GCN2 deficient mice, in which both eIF2α phosphorylation and ATF4 levels are reduced, the threshold for long-lasting long-term potentiation (L-LTP) and LTM in hippocampus is lowered and it is associated with an improved spatial memory of weak conditioning (Costa-Mattioli et al., 2005). This model is supported by the increase of ATF4 expression upon treatment with an inhibitor of eIF2α phosphatases, Sal003, which leads to an impairment of L-LTP and LTM.

[0213] Accordingly, in some embodiments, a compound or salt thereof described herein or a composition described herein may be used in treating or preventing memory loss.

[0214] Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer’s disease (AD) patients and Alzheimer’s disease model mice. Suppressing GCN2 prevents amyloid-β-induced synaptic plasticity impairments by diminishing eIF2α phosphorylation. Senile plaques are primarily composed of β-amyloid peptides (Aβ) derived from amyloid precursor protein (APP) that has undergone proteolytic processing by β-secretase (BACE-1) and γ-secretase. It was also reported that BACE-1 levels are translationally increased by phosphorylation of elF2α (O'Connor et al., 2008). Inhibition of GCN2 under such disease conditions that promote activation of γ-secretase or induction of BACE-1 with consequence of accumulation of Aβ and plaque formation in the brain would provide a valuable avenue to cope with or even stop the progression of neurodegenerative diseases.

[0215] Deletion of GCN2 prevented impairments of synaptic plasticity and defects in spatial memory in mice that express familial AD–related mutations in amyloid precursor protein (APP) and presenilin-1 (PS1). PS1 is essential for γ-secretase activity and GCN2 / eIF2α / ATF4 signalling has an important role in the regulation of γ-secretase activity in autophagy impaired cells (Ohata et al., 2010).

[0216] Furthermore, hippocampal LTP deficits in APP-PS1 mice were normalized in APP-PS1 GCN2-deficient mice. The impairments in spatial learning and memory displayed by the APP-PS1 mice were prevented in the APP-PS1 GCN2-deficient mice as observed in a Morris Water Maze task by decreased escape latency, increased platform crossings as well as target quadrant occupancy that were close to those displayed by wild-type mice (Ma et al.,2013). Taken together, these findings indicate that genetic removal of the eIF2α kinase GCN2 prevents Alzheimer’s disease–associated LTP failure and spatial memory impairments.

[0217] Accordingly, in some embodiment, a compound or salt thereof described herein or a composition described herein may be used in treating neurodegenerative diseases.

[0218] Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen / nutrient deprivation sensed by GCN2 and orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Neovascularization in the retina and the choroid is a major cause of vision loss in severe eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Amino acid restriction triggers angiogenesis via GCN2 / ATF4 regulation of VEGF and hydrogen sulfide production (Longchamp et al., 2018).

[0219] Yet, retinal neovascularization is causally and dynamically associated with vasodegeneration, ischemia, and vascular remodeling in retinal tissues (Zhang et al., 2015). ATF4 has been shown to function as an oxygen sensor and interacts with HIF-1α to regulate VEGF production (Zhong et al., 2012). Global knockout of ATF4 disturbs lens development, resulting in microphthalmia (Masuoka and Townes, 2002). Genetic inhibition of ATF4 activity attenuates diabetic-induced retinal inflammation and vascular leakage, suggesting that up-regulation of ATF4 contributes to retinal inflammation and endothelial barrier dysfunction in diabetic retinopathy (Chen et al., 2012).

[0220] Accordingly, in some embodiment, a compound or salt thereof described herein or a composition described herein may be used in treating ocular diseases.

[0221] Since there is accumulating evidence showing that the GCN2 pathway strongly influences the function of the immune system, the present invention encompasses the use of GCN2 modulators for the treatment or prevention of immune related disorders. In some embodiment, a compound or salt thereof described herein or a composition described herein may be used in treating or preventing immune related disorders. In some embodiment, a compound or salt thereof described herein or a composition described herein may be used in treating or preventing an autoimmune disease selected from the group consisting of arthritis, graft-versus-host disease, Crohn’s disease, multiple sclerosis, lupus, type 1 diabetes mellitus, rheumatoid arthritis, Grave’s disease, autoimmune hemolytic anemia, Wegener’sgranulomatosis, ankylosing spondylitis, aplastic anemia, Behcet’s disease, hyper IgE syndrome, idiopathic thrombocytopenia purpura, Myasthenia gravis and psoriasis.

[0222] In some embodiment, a compound or salt thereof described herein or a composition described herein may be used in transplantation proceeding to treat organ rejection, myeloablative and non-myeloablative bone marrow transplant rejection.

[0223] In some embodiment, a compound or salt thereof described herein or a composition described herein may be used to inhibit the phosphorylation of GCN2. In some embodiments, a compound or salt thereof described herein or a composition described herein can be used to promote the recovery protein synthesis under amino acid deprived condition. In some embodiments, a compound or salt thereof described herein or a composition described herein can be used to enhance protein synthesis, and thus can be used in diseases or disorders that are mediated by a decrease in protein synthesis such as muscle atrophy, muscle dystrophy, cachexia, synaptic plasticity and long-term memory, among others.

[0224] In accordance with the present disclosure, in some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, bovine, ovine, porcine, equine, canine, feline, rabbit, or rodent. In some embodiments, the individual is a human. In some embodiments, the individual has any of the diseases or disorders disclosed herein. In some embodiments, the individual is a risk for developing any of the diseases or disorders disclosed herein.

[0225] Also provided herein are uses of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is for the treatment of a disorder or disease described herein. In some embodiments, the manufacture of a medicament is for the prevention and / or treatment of a disorder or disease mediated by the GCN2 pathway.

[0226] In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method as either a stand-alone therapy, or as a conjunctive therapy with other agents that are either palliative (e.g., agents that relieve the symptoms of the disorder to be treated), and / or agents that target the etiology of the disorder. Compounds or compositions of the present invention may be used or administered incombination with a second therapeutic agent. Compounds or compositions of the present invention may be used or administered in combination with an anticancer agent, anti- angiogenesis agent or an agent that targets an immune checkpoint protein. Compounds or compositions of the present invention may be used or administered in combination with a second therapeutic agent selected from: PEG-arginase, asparaginase, anti-angiogenic factors, cysteinase or sulfasalazine.

[0227] As provided herein, compounds or salts thereof described herein and compositions described herein may be administered with an agent to treat any of the diseases and disorders disclosed herein. In some embodiments, the agent is an anti-angiogenesis agent. In some embodiments, the agent is an anticancer agent. In some embodiments, the agent targets an immune checkpoint protein.

[0228] In some embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are sequentially administered, concurrently administered or simultaneously administered. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or less, such as about any of 10, 5, or 1 minutes or less. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or more, such as about any of 20, 30, 40, 50, 60, or more minutes. Either (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent may be administered first. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered simultaneously.

[0229] Provided herein is a method of enhancing an immune response in an individual comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent that targets an immune checkpoint protein. In some embodiments, the individual has cancer. In some embodiments, the enhanced immune response is directed to a tumor or cancerous cell.

[0230] Also provided herein are methods of treating cancer in an individual in need thereof comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent that targets an immune checkpoint protein, wherein an immune response of the individual is increased.

[0231] In some embodiments, the agent is an anticancer agent. In some embodiments, anticancer agent is an ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxil), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based antineoplastic drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g. doxorubicin), a pyrimidine analog (e.g.5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), or an agent that modulates the Unfolded Protein Response or the Integrated Stress Response (e.g. an IRE1 / XBP1 inhibitor or a PERK inhibitor). In some embodiments, the anticancer agent is oxaliplatin, 5-fluorouracil, or gemcitabine. In some embodiments, the anticancer agent is an immune-check point inhibitor, or an agent that is used in immune oncology.

[0232] In some embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to an individual with cancer to increase sensitivity to one or more anticancer treatments.

[0233] In some embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to an individual with cancer to increase sensitivity to radiation. In some embodiments, provided herein are methods of treating cancer in an individual in need thereof comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) radiation.

[0234] In some embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to an individual with cancer to increase sensitivity to one or more anticancer agents. In some embodiments, the anticancer agent is an ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxil), a Cox-2 inhibitor (e.g.,celecoxib), a platinum-based antineoplastic drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g. doxorubicin), a pyrimidine analog (e.g.5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), or an agent that modulates the Unfolded Protein Response or the Integrated Stress Response (e.g. an IRE1 / XBP1 inhibitor or a PERK inhibitor). In some embodiments, the anticancer agent is oxaliplatin, 5-fluorouracil, or gemcitabine. In some embodiments, the anticancer agent is an immune-check point inhibitor, or an agent that is used in immune oncology.

[0235] The invention can be further understood by reference to the following examples, which are provided by way of illustration and are not meant to be limiting.

[0236] All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties. EXAMPLES Synthetic Examples

[0237] The invention will now be illustrated, but not limited, by reference to the following examples. Some compounds of Formula (I) and derivatives or synthetic intermediates thereof can be prepared in accordance with synthetic methods known to the skilled person. In some embodiments, the invention provides a process for the preparation of a compound as defined in Formula (I) above. Certain compounds of the invention may be prepared according to the methods described in WO 2021 / 165346. Example S-1: Synthesis of 6-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 36) and stereoisomers (Compound 37 and Compound 38) O12

[0238] Into a 50-mL round-bottom was placed 4-(benzylsulfanyl)-6-chloro-2,3- dihydroinden-1-one (840 mg, 2.909 mmol, 1 equiv), AcOH (8 mL), H2O (1.6 mL), NCS(1165.19 mg, 8.727 mmol, 3.0 equiv). The resulting solution was stirred for 2 h at 20 °C . The mixture was neutralized to pH 7 with NaHCO3. The resulting mixture was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 6-chloro-1-oxo-2,3-dihydroindene-4-sulfonyl chloride (960 mg, 62.25%) as a yellow syrup. FOO Cl

[0239] Into a 50-mL round-bottom was placed 3-bromo-2,4-difluoroaniline (376.62 mg, 1.811 mmol, 1.0 equiv), DCM (10 mL), pyridine (859.33 mg, 10.866 mmol, 6.0 equiv), 6- chloro-1-oxo-2,3-dihydroindene-4-sulfonyl chloride (960 mg, 1.811 mmol, 1 equiv, 50%). The resulting solution was stirred for 2 h at 20 °C . The resulting solution was extracted with 3x10 mL of dichloromethane. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0% ethyl acetate up to 50% in 10 min). The collected fractions were combined and concentrated under vacuum. This resulted in N-(3- bromo-2,4-difluorophenyl)-6-chloro-1-oxo-2,3-dihydroindene-4-sulfonamide (432 mg, 54.64%) as a brown solid.

[0240] LCMS of 4: RT = 1.203 min, m / z 433.9, 435.9 [M-H]- FBrH45

[0241] Into a 50-mL round-bottom was placed N-(3-bromo-2,4-difluorophenyl)-6-chloro- 1-oxo-2,3-dihydroindene-4-sulfonamide (432 mg, 0.989 mmol, 1 equiv), MeOH (4.5 mL), NaBH4(74.85 mg, 1.978 mmol, 2.0 equiv). The resulting solution was stirred for 2 h at 20 °C . The reaction was then quenched by the addition of 5 mL of NH4Cl. The resulting solution was extracted with 3x10 mL of ethyl acetate The collected fractions were combined andconcentrated under vacuum. This resulted in N-(3-bromo-2,4-difluorophenyl)-6-chloro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (442 mg, 91.66%) as a brown solid.

[0242] LCMS of 5: RT = 1.203 min, m / z 435.9, 437.9 [M-H]- FBrOH

[0243] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (200 mg, 0.410 mmol, 1 equiv, 90%), dioxane (2 mL), H2O (0.2 mL), 2-fluoro- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (134.97 mg, 0.492 mmol, 1.2 equiv), K2CO3 (170.13 mg, 1.230 mmol, 3.0 equiv), RuPhos Palladacycle Gen.3 (34.32 mg, 0.041 mmol, 0.1 equiv). The resulting solution was stirred for 16 h at 100 °C . The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. The collected fractions were combined and concentrated under vacuum. This resulted in 6-chloro-N-[2,4-difluoro-3-(2-fluoroquinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (62 mg, 29.87%) as a brown solid.

[0244] LCMS of 7: RT = 1.133 min, m / z 504.0 [M-H]- OH F7

[0245] Into a 8-mL vial was placed 6-chloro-N-[2,4-difluoro-3-(2-fluoroquinazolin-6- yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (62 mg, 0.123 mmol, 1 equiv), DMSO (1 mL), DIEA (79.20 mg, 0.615 mmol, 5.0 equiv), 1-methylpiperidin-4-amine (18.19 mg, 0.160 mmol, 1.3 equiv). The resulting solution was stirred for 2 h at 100 °C . Thecrude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. Lyophilization. This resulted in 6-chloro-N-(2,4-difluoro-3-(2-[(1-methylpiperidin-4- yl)amino]quinazolin-6-ylphenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (8.9 mg, 11.21%) as a off-white solid.

[0246] LCMS: RT = 1.060 min, m / z 600.2 [M+H]+

[0247] 1H NMR:1H NMR (300 MHz, CD3OD) δ 9.05 (s, 1H), 7.70 (s, 1H), 7.68 – 7.44 (m, 4H), 7.41 (dd, J = 9.0, 5.8 Hz, 1H), 7.06 (t, J = 8.8 Hz, 1H), 5.15 (t, J = 6.7 Hz, 1H), 4.02 (s, 1H), 3.28 – 3.21 (m, 1H), 2.97 (dd, J = 15.9, 8.7 Hz, 3H), 2.36 (d, J = 18.9 Hz, 6H), 2.13 (d, J = 13.2 Hz, 2H), 2.01 – 1.82 (m, 2H), 1.72 (d, J = 11.5 Hz, 2H). F OH N OHCl

[0248] The 200 mg of 6-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide was further purified by Chiral-Prep-HPLC with the following conditions: Instrument Name: SHIMADZU LC-09, LC parameters: Pump Mode: Binary gradient, Start Conc. of Pump B: 18.0%, Total Flow: 20 mL / min, Phase A: n-Hexane / DCM=1 / 1,, Phase B: MeOH / ACN=1 / 1(20mM NH3), Column Name: CHIRALCEL OD-3, 4.6*100 mm, 3μm, Column Temp: 25oC, Wavelength: from 190 nm to 500 nm.

[0249] This is the isomer eluted first and the chirality on carbon atom moiety of this isomer (t = 3.164 min) was assumed as S, this resulted in (1S)-6-chloro-N-(2,4-difluoro-3-{2-[(1-methylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-1-hydroxy-2,3-dihydro-1H-indene- 4-sulfonamide (50.4 mg, 24.70%) as off-white solid.

[0250] This is the isomer eluted second and the chirality on carbon atom moiety of this isomer (t = 3.900 min) was assumedas R, this resulted in (1R)-6-chloro-N-(2,4-difluoro-3-{2- [(1-methylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-1-hydroxy-2,3-dihydro-1H-indene- 4-sulfonamide (53.1 mg, 24.16%) as off-white solid.

[0251] LCMS of (S)-6-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide: RT = 1.100 min, m / z 600.2 [M+H]+

[0252] 1H NMR of (S)-6-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide: 1H NMR (300 MHz, Methanol-d4) δ 9.06 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 4.5 Hz, 3H), 7.46 (td, J = 8.8, 5.7 Hz, 1H), 7.09 (td, J = 9.1, 1.8 Hz, 1H), 5.15 (t, J = 6.7 Hz, 1H), 4.06 (s, 1H), 3.24 (td, J = 8.7, 4.0 Hz, 1H), 3.04 (t, J = 11.0 Hz, 2H), 2.93 (dd, J = 17.2, 8.2 Hz, 1H), 2.46 (s, 3H), 2.16 (d, J = 13.4 Hz, 2H), 1.97 – 1.70 (m, 2H).

[0253] LCMS of (R)-6-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide: RT = 1.685 min, m / z 600.2 [M+H]+

[0254] 1H NMR of (R)-6-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4- yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide: 1H NMR (300 MHz, Methanol-d4) δ 9.07 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 3.9 Hz, 3H), 7.53 – 7.40 (m, 1H), 7.17 – 7.05 (m, 1H), 5.15 (t, J = 6.7 Hz, 1H), 4.10 (s, 1H), 3.18 (dd, J = 19.5, 8.6 Hz, 3H), 2.94 (dt, J = 16.9, 7.9 Hz, 1H), 2.62 (s, 2H), 2.55 (s, 3H), 2.46 (s, 1H), 2.18 (s, 2H), 1.88 (dd, J = 13.3, 6.9 Hz, 1H), 1.80 (s, 2H). Example S-2: Synthesis of N-(2,4-difluoro-3-(2-((1-methylpiperidin-4- yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 47)F OOOH

[0255] Into an 8 mL vial, was placed N-(1-methylpiperidin-4-yl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (50 mg, 0.136 mmol, 1 equiv), N-(3-bromo-2,4- difluorophenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (85.98 mg, 0.204 mmol, 1.5 equiv), Pd(dppf)Cl2 (4.97 mg, 0.007 mmol, 0.05 equiv), K2CO3 (56.29 mg, 0.408 mmol, 3.0 equiv), dioxane (1 mL) and H2O (0.1 mL). The resulting mixture was stirred for 16 h at 90oC under nitrogen atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.5% NH4HCO3) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. This resulted in N-(2,4-difluoro- 3-{2-[(1-methylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-6-fluoro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (5.2 mg, 6.13%) as a off-white solid.

[0256] LCMS: RT = 2.595 min, m / z 584.2 [M+H]+

[0257] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 7.70 (s, 1H), 7.59 (t, J = 7.2 Hz, 2H), 7.49 – 7.31 (m, 3H), 7.06 (t, J = 9.0 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.03 (s, 2H), 3.01 (s, 1H), 2.99 – 2.86 (m, 2H), 2.45 (s, 2H), 2.40 (s, 4H), 2.37 (s, 1H), 2.13 (d, J = 12.7 Hz, 2H), 1.96 – 1.84 (m, 1H), 1.73 (d, J = 12.0 Hz, 2H). Example S-3: Synthesis of N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4- yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 46)F OOO OH1

[0258] Into an 8 mL vial were added N-[1-(2-methoxyethyl)piperidin-4-yl]-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (80 mg, 0.194 mmol, 1 equiv), N-(3- bromo-2,4-difluorophenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (122.88 mg, 0.291 mmol, 1.5 equiv), K2CO3 (80.44 mg, 0.582 mmol, 3.0 equiv), dioxane (1.0 mL) , H2O (0.1 mL) and Pd(dppf)Cl2(7.10 mg, 0.010 mmol, 0.05 equiv) at 100oC at 2 h. The crude product was purified by reverse phase flash with the following conditions (Prep- HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 60.0% in 7 min). This resulted in N-[2,4- difluoro-3-(2-{[1-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-6-fluoro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (16.3 mg, 12.85%) as a off-white solid.

[0259] LCMS: RT = 1.065 min, m / z 600.2 [M+H]+

[0260] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 7.70 (s, 1H), 7.65 – 7.54 (m, 2H), 7.41 (ddd, J = 14.7, 8.9, 2.9 Hz, 2H), 7.34 (dd, J = 8.1, 2.5 Hz, 1H), 7.10 – 7.01 (m, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.02 (dt, J = 10.9, 6.5 Hz, 1H), 3.60 (t, J = 5.6 Hz, 2H), 3.38 (s, 3H), 3.23 (dd, J = 7.7, 4.5 Hz, 1H), 3.06 (d, J = 11.9 Hz, 3H), 2.93 (dt, J = 16.8, 7.7 Hz, 1H), 2.69 (t, J = 5.6 Hz, 2H), 2.47 (ddd, J = 16.0, 7.6, 3.7 Hz, 1H), 2.38 (q, J = 11.6, 10.6 Hz, 2H), 2.11 (d, J = 12.9 Hz, 2H), 1.96 – 1.82 (m, 1H), 1.79 – 1.65 (m, 2H). Example S-4: Synthesis of (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(2- methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (Compound 40)Br O

[0261] Into a 1000-mL three-necked flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-6-chloro-2,3-dihydroinden-1-one (25 g, 101.833 mmol, 1 equiv), dioxane (250 mL), DIEA (39.48 g, 305.499 mmol, 3.0 equiv), benzyl mercaptan (13.91 g, 112.016 mmol, 1.1 equiv), Xantphos (3.54 g, 6.110 mmol, 0.06 equiv), Pd2(dba)3 (2.80 g, 3.055 mmol, 0.03 equiv). The resulting solution was stirred for 16 h at 100 °C. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (15 / 85). The collected fractions were combined and concentrated under vacuum. This resulted in 4-(benzylsulfanyl)- 6-chloro-2,3-dihydroinden-1-one (31 g, 105.41%) as a yellow solid.

[0262] LCMS of 10: RT = 1.377 min, m / z 289.0, 291.0 [M+H]+O0

[0263] Into a 1000-mL three-necked flask was placed 4-(benzylsulfanyl)-6-chloro-2,3- dihydroinden-1-one (31 g, 107.344 mmol, 1 equiv), AcOH (310 mL), H2O (62 mL). To the above mixture was added NCS (43.00 g, 322.032 mmol, 3.0 equiv) in portions at 0 °C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with saturated sodium bicarbonate (2x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in crude 6-chloro-1-oxo-2,3- dihydroindene-4-sulfonyl chloride (39 g, 68.52%) as a light yellow solid.FOO Cl

[0264] Into a 1000-mL three-necked flask was placed 3-bromo-2,4-difluoroaniline (14.52 g, 69.785 mmol, 1.0 equiv), DCM (370 mL), pyridine (49.68 g, 628.065 mmol, 9.0 equiv), crude 6-chloro-1-oxo-2,3-dihydroindene-4-sulfonyl chloride (37 g, 69.785 mmol, 1 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was extracted with dichloromethane (2 x 400 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1 / 4). The collected fractions were combined and concentrated under vacuum. This resulted in N-(3-bromo-2,4-difluorophenyl)- 6-chloro-1-oxo-2,3-dihydroindene-4-sulfonamide (23 g, 75.48%) as a brown solid.

[0265] LCMS of 13: RT = 1.210 min, m / z 433.9, 435.9 [M-H]+FBrH13 14

[0266] Into a 500-mL three-necked flask was placed N-(3-bromo-2,4-difluorophenyl)-6- chloro-1-oxo-2,3-dihydroindene-4-sulfonamide (23 g, 52.674 mmol, 1 equiv), ACN (161 mL), HCOOH (7.27 g, 158.022 mmol, 3.0 equiv), Et3N (10.66 g, 105.348 mmol, 2.0 equiv). To the above mixture was added (R,R)-TS-DENEB (1.03 g, 1.580 mmol, 0.03 equiv) at 0 °C. The resulting solution was stirred for 3 h at 30 °C. The reaction was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (3 / 7). The collected fractions were combined and concentrated under vacuum. This resulted in (1R)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (23 g, 99.54%) as a brown solid.

[0267] LCMS of 14: RT = 1.516 min, m / z 437.9 [M+H]+Boc N Br Cl1 3

[0268] Into a 1 L vial were added 6-bromo-2-chloroquinazoline (20 g, 82.139 mmol, 1 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (24.68 g, 123.208 mmol, 1.5 equiv) ,DIEA (63.70 g, 492.834 mmol, 6.0 equiv) and DMSO (200 mL) ,the reaction mixture was stirred for 4 h at 130℃. After completion of reaction, the reaction mixture was quenched by addition of water 200 ml. The aqueous layer was extracted with ethyl acetate (300 ml x 3). The combined organic phase was washed with brine (200 ml x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. Then, the residue was purified by trituration with petroleum ether (300 ml). The precipitated solids were collected by filtration. To afford tert-butyl 4-[(6-bromoquinazolin-2- yl)amino]piperidine-1-carboxylate (26 g, 77.71%) as a gray solid.

[0269] LCMS: RT = 0.941 min, m / z 407.1 [M+H]+Bo3 5

[0270] Into a 500-mL round-bottom flask, and maintained with an inert atmosphere of nitrogen, were added tert-butyl 4-[(6-bromoquinazolin-2-yl)amino]piperidine-1-carboxylate (14 g, 34.372 mmol, 1 equiv), bis(pinacolato)diboron (13.09 g, 51.558 mmol, 1.5 equiv), KOAc (6.75 g, 68.744 mmol, 2.0 equiv), dioxane (140 mL), Pd(dppf)Cl2 (1.26 g, 1.719 mmol, 0.05 equiv). The reaction mixture was stirred for 4 h at 90 ℃. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:5). To afford tert-butyl 4-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1-carboxylate (15 g, 96.04%) as a light yellow solid.

[0271] LCMS: RT = 1.080 min, m / z 455.3 [M+H]+F OO)BoOH

[0272] Into a 500-mL round-bottom flask, and maintained with an inert atmosphere of nitrogen, were added (1R)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide (20 g, 45.592 mmol, 1.00 equiv), tert-butyl 4-{[6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1-carboxylate (20.72 g, 45.592 mmol, 1 equiv), K2CO3(18.90 g, 136.776 mmol, 3.0 equiv), dioxane (200 mL), H2O (20 mL), Pd(dppf)Cl2(1.67 g, 2.280 mmol, 0.05 equiv). The reaction mixture was stirred for 2 h at 100 ℃. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). To afford tert-butyl 4-[(6-{3-[(1R)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido]- 2,6-difluorophenyl}quinazolin-2-yl)amino]piperidine-1-carboxylate (19 g, 60.73%) as a brown yellow solid.

[0273] LCMS: RT = 0.744 min, m / z 686.3 [M+H]+) BoOH67

[0274] Into a 500-mL round-bottom flask, were added tert-butyl 4-[(6-{3-[(1R)-6-chloro- 1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl}quinazolin-2- yl)amino]piperidine-1-carboxylate (19 g, 27.690 mmol, 1 equiv), DCM (190 mL) and TFA (38 mL, 511.597 mmol, 18.48 equiv). The reaction mixture was stirred for 1 h at rt. The resulting mixture was concentrated under reduced pressure. To afford (1R)-6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (26 g, 160.22%) as a light yellow oil.

[0275] LCMS: RT = 0.751 min, m / z 586.2 [M+H]+F TFA O F ) HN OH

[0276] Into a 1000-mL round-bottom flask, were added (1R)-6-chloro-N-{2,4-difluoro-3- [2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (33 g, 56.309 mmol, 1 equiv), DMF (330 mL), K2CO3(23.35 g, 168.927 mmol, 3.0 equiv) and 1-chloro-2-methoxyethane (10.65 g, 112.618 mmol, 2.0 equiv). The reaction mixture was stirred for 16 h at 70 ℃. The reaction was added 1-chloro-2-methoxyethane (5.32 g, 56.309 mmol, 1.0 equiv), the reaction mixture was stirred for 4 h at 70 ℃. After cooled to room temperature, the reaction mixture was filtered through a Celite pad. The residue was diluted with water, the resulting solution was extracted with 3 x 200 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The reaction mixture was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH4HCO3) and MeCN (15.0% MeCN up to 65.0% in 15 min). Lyophilization. To afford (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(2- methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (12 g, 32.65%) as a off white solid.

[0277] LCMS: RT = 1.152 min, m / z 644.2 [M+H]+

[0278] 1H NMR: H-NMR (400 MHz, CD3OD) δ 9.05 (s, 1H), 7.69 (s, 1H), 7.64 – 7.54 (m, 4H), 7.44 (td, J = 8.9, 5.7 Hz, 1H), 7.08 (td, J = 9.1, 1.7 Hz, 1H), 5.15 (t, J = 6.7 Hz, 1H), 4.08 – 3.98 (m, 1H), 3.60 (t, J = 5.6 Hz, 2H), 3.38 (s, 3H), 3.26 (ddd, J = 17.4, 8.6, 4.1 Hz, 1H), 3.09 (d, J = 12.1 Hz, 3H), 2.95 (dt, J = 16.9, 8.0 Hz, 1H), 2.72 (t, J = 5.6 Hz, 2H), 2.51 – 2.36 (m, 3H), 2.12 (d, J = 12.9 Hz, 2H), 1.95 – 1.82 (m, 1H), 1.76 (d, J = 13.6 Hz, 1H), 1.71 (s, 1H).Example S-5: Synthesis of 6-chloro-N-(3-(2-((1-ethylpiperidin-4-yl)amino)quinazolin-6- yl)-2,4-difluorophenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 35) F OHBr

[0279] Into a 8 mL vial with an inert atmosphere of nitrogen were added N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (100 mg, 0.228 mmol, 1 equiv), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (68.73 mg, 0.251 mmol, 1.1 equiv), RuPhos Palladacycle Gen.3 (19.07 mg, 0.023 mmol, 0.1 equiv), K2CO3 (94.52 mg, 0.684 mmol, 3 equiv) and dioxane(1mL), H2O (0.1mL) (10:1) at 100°C for 2 h. In the reaction system, 82% P in LCMS, step1 directly went to the next step without purification.

[0280] LCMS: m / z 506.0 [M+H]+OH F3

[0281] Into a 8 mL vial were added 6-chloro-N-[2,4-difluoro-3-(2-fluoroquinazolin-6- yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (100 mg, 0.198 mmol, 1 equiv), 1-ethylpiperidin-4-amine (25.34 mg, 0.198 mmol, 1 equiv), DIEA (76.64 mg, 0.594 mmol, 3 equiv) and DMSO at 100 °C for 2 h. The crude product was purified by reverse phase flash. This resulted in 6-chloro-N-(3-{2-[(1-ethylpiperidin-4-yl)amino]quinazolin-6-yl}-2,4- difluorophenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (11 mg, 10.21%) as a off white solid.

[0282] LCMS: RT = 1.147 min, m / z 614.2 [M+H]+

[0283] 1H NMR: 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.75 (s, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 2.0 Hz, 1H), 7.51 (s, 1H), 7.21 (q, J = 8.5 Hz, 1H), 7.04 (s, 1H), 5.51 (d, J = 5.7 Hz, 1H), 5.03 (q, J = 6.7 Hz, 1H), 3.97 (s, 1H), 2.81 (dt, J = 16.8, 8.2 Hz, 1H), 2.31 (s, 1H), 1.99 (s, 2H), 1.73 (dt, J = 13.0, 6.9 Hz, 1H), 1.65 (s, 2H), 1.24 (s, 2H), 1.09 (t, J = 7.1 Hz, 3H). Example S-6: Synthesis of 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin- 3-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 32) Br Cl

[0284] Into a 8-mL vial was placed 6-bromo-2-chloroquinazoline (200 mg, 0.821 mmol, 1 equiv), n-BuOH (2 mL), DIEA (636.97 mg, 4.926 mmol, 6.0 equiv), tert-butyl 3- aminopiperidine-1-carboxylate (246.76 mg, 1.232 mmol, 1.5 equiv). The resulting solution was stirred for 4 h at 130 °C. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. The collected fractions were combined and concentrated under vacuum. This resulted in tert-butyl 3-[(6-bromoquinazolin- 2-yl)amino]piperidine-1-carboxylate (239 mg, 71.44%) as a yellow syrup.

[0285] LCMS of 3: RT = 1.523 min, m / z 407.1, 409.1 [M+H]+O O B

[0286] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 3-[(6-bromoquinazolin-2-yl)amino]piperidine-1-carboxylate (239 mg, 0.587 mmol, 1 equiv), dioxane (2.4 mL), KOAc (115.17 mg, 1.174 mmol, 2.0 equiv), bis(pinacolato)diboron (163.91 mg, 0.646 mmol, 1.1 equiv), Pd(dppf)Cl2(21.47 mg, 0.029 mmol, 0.05 equiv). The resulting solution was stirred for 16 h at 90 °C . The solid was filtered out. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0% ethyl acetate up to 50% in 10 min). The collected fractions were combined and concentrated under vacuum. This resulted in tert-butyl 3-([6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]aminopiperidine-1-carboxylate (252 mg, 94.52%) as a yellow syrup.

[0287] LCMS of 4: RT = 1.443 min, m / z 455.3 [M+H]+BH Step3 H 45

[0288] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 3-([6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl]aminopiperidine-1-carboxylate (252 mg, 0.555 mmol, 1 equiv), DCM (2.5 mL), HCl (2.5 mL, 82.282 mmol, 148.36 equiv). The resulting solution was stirred for 1 h at 25 °C . The reaction was concentrated under vacuum. This resulted in N-(piperidin-3-yl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (208 mg, 95.28%) as a yellow syrup.

[0289] LCMS of 5: RT = 0.883 min, m / z 355.2 [M+H]+HN

[0290] Into a 8-mL vial was placed N-(piperidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-amine (208 mg, 0.528 mmol, 1 equiv, 90%), ACN (2 mL), K2CO3 (292.12 mg, 2.112 mmol, 4.0 equiv), 2-bromoethyl methyl ether (110.17 mg, 0.792 mmol, 1.5 equiv). The resulting solution was stirred for 4 h at 60 °C . The solid was filtered out. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (0% MeOH up to 20% in 10 min). The collected fractions were combined and concentrated under vacuum. This resulted in N-[1-(2-methoxyethyl)piperidin-3-yl]-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (117 mg, 53.70%) as a yellow syrup.

[0291] LCMS of 6: RT = 0.197 min, m / z 413.2 [M+H]+OH Me6

[0292] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (76.60 mg, 0.175 mmol, 1.0 equiv), DMSO (1 mL), H2O (0.1 mL), N-[1-(2- methoxyethyl)piperidin-3-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- amine (72 mg, 0.175 mmol, 1.0 equiv), K2CO3 (72.40 mg, 0.525 mmol, 3.0 equiv), RuPhos Palladacycle Gen.3 (7.30 mg, 0.009 mmol, 0.05 equiv). The resulting solution was stirred for 3 h at 100 °C . The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. Lyophilization. This resulted in 6-chloro-N-[2,4-difluoro-3-(2-([1-(2-methoxyethyl)piperidin-3-yl]aminoquinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide; formic acid (24.0 mg, 19.82%) as a off-white solid.

[0293] LCMS: RT = 1.073 min, m / z 644.2 [M+H]+

[0294] 1H NMR:1H NMR (300 MHz, CD3OD) δ 9.09 (s, 1H), 7.72 (s, 1H), 7.60 (d, J = 4.3 Hz, 4H), 7.47 (td, J = 8.9, 5.8 Hz, 1H), 7.11 (td, J = 9.2, 1.9 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.42 – 4.30 (m, 1H), 3.67 (t, J = 5.3 Hz, 2H), 3.46 (d, J = 11.3 Hz, 1H), 3.38 (s, 3H), 3.25 (dq, J = 13.5, 4.7, 4.2 Hz, 1H), 3.13 (s, 1H), 3.02 (d, J = 5.7 Hz, 2H), 2.93 (dd, J = 17.4, 8.2 Hz, 1H), 2.68 (d, J = 12.3 Hz, 2H), 2.45 (dtd, J = 11.9, 7.5, 3.9 Hz, 1H), 2.05 (s, 1H), 1.97 (d, J = 4.3 Hz, 1H), 1.88 (dd, J = 12.6, 7.1 Hz, 2H), 1.65 (d, J = 10.8 Hz, 1H). Example S-7: Synthesis of 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxy-2- methylpropyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (Compound 27) HNStep1 c 1 3

[0295] Into a 50-mL round-bottom flask was placed 2-methoxy-2-methylpropanoic acid (0.59 g, 4.993 mmol, 1.0 equiv), DMF (10 mL), DIEA (1.94 g, 14.979 mmol, 3.0 equiv), HATU (2.85 g, 7.490 mmol, 1.5 equiv), 2-methoxy-2-methylpropanoic acid (0.59 g, 4.993 mmol, 1.0 equiv). The resulting solution was stirred for 1 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.1% FA) and ACN, 20% to 98% gradient in 6 min; detector, UV 220 nm. The collected fractions were combined and concentrated under vacuum. This resulted in tert-butyl N-[1-(2-methoxy-2-methylpropanoyl)piperidin-4- yl]carbamate (1.1 g, 73.34%) as a off-white solid.

[0296] LCMS of 3: RT = 1.017 min, m / z 301.2 [M+H]+O O c

[0297] Into a 40-mL vial was placed tert-butyl N-[1-(2-methoxy-2- methylpropanoyl)piperidin-4-yl]carbamate (600 mg, 1.997 mmol, 1 equiv), THF (12 mL), BH3-THF (6.99 mL, 6.990 mmol, 3.5 equiv). The resulting solution was stirred for 1 h at 75 °C. The reaction was quenched with MeOH (10 mL) at room temperature. The reaction was concentrated under vacuum. The resulting mixture was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with saturated brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl N-[1-(2-methoxy-2-methylpropyl)piperidin-4-yl]carbamate (330 mg, 57.69%) as a off-white viscous oil.

[0298] LCMS of 4: RT = 0.617 min, m / z 287.2 [M+H]+24 5

[0299] Into a 40-mL vial was placed tert-butyl N-[1-(2-methoxy-2- methylpropyl)piperidin-4-yl]carbamate (330 mg, 1.152 mmol, 1 equiv), DCM (3.5 mL), TFA (0.7 mL). The resulting solution was stirred for 2 h at room temperature. The reaction was concentrated under vacuum. This resulted in 1-(2-methoxy-2-methylpropyl)piperidin-4- amine (280 mg, 65.22%) as a off-white viscous oil.

[0300] LCMS of 5: RT = 0.177 min, m / z 187.2 [M+H]+

[0301] Into a 40-mL vial was placed 1-(2-methoxy-2-methylpropyl)piperidin-4-amine (280 mg, 0.751 mmol, 3.0 equiv, 50%), DMSO (3 mL), DIEA (323.76 mg, 2.503 mmol, 10.0 equiv), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (68.66 mg, 0.250 mmol, 1.0 equiv). The resulting solution was stirred for 2 h at 130 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% NH3H2O) and ACN, 20% to 98% gradient in 6 min; detector, UV 254 nm. The collected fractions were combined and concentrated under vacuum. This resulted in N-[1-(2-methoxy-2-methylpropyl)piperidin-4-yl]-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (140 mg, 63.45%) as a off-white solid.

[0302] LCMS of 7: RT = 0.563 min, m / z 359.1 [M+H]+O OHH Step5 C 7

[0303] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-[1-(2-methoxy-2-methylpropyl)piperidin-4-yl]-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (140 mg, 0.159 mmol, 1.4 equiv, 50%), dioxane (2 mL), H2O (0.2 mL), N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamide (49.80 mg, 0.114 mmol, 1.0 equiv), K2CO3(47.07 mg, 0.341 mmol, 3.0 equiv), Pd(dppf)Cl2(4.15 mg, 0.006 mmol, 0.05 equiv). The resulting solution was stirred for 2 h at 100 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water(0.05% NH3H2O) and ACN, 20% to 98% gradient in 6 min; detector, UV 254 nm. Lyophilization. This resulted in 6-chloro-N-[2,4-difluoro-3-(2-([1-(2-methoxy-2- methylpropyl)piperidin-4-yl]aminoquinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (10.4 mg, 12.81%) as a off-white solid.

[0304] LCMS: RT = 2.935 min, m / z 672.2 [M+H]+

[0305] 1H NMR:1H NMR (300 MHz, CD3OD) δ 9.05 (s, 1H), 7.69 (s, 1H), 7.65 – 7.53 (m, 4H), 7.51 – 7.37 (m, 1H), 7.07 (t, J = 9.0 Hz, 1H), 5.15 (t, J = 6.9 Hz, 1H), 3.98 (s, 1H), 3.25 (s, 4H), 3.08 – 2.96 (m, 2H), 2.96 – 2.85 (m, 1H), 2.45 (d, J = 13.2 Hz, 5H), 2.04 (d, J = 11.5 Hz, 2H), 1.89 (dd, J = 13.4, 6.7 Hz, 1H), 1.71 (d, J = 10.7 Hz, 2H), 1.23 (s, 6H). Example S-8: Synthesis of (R)-6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-(((1R,3R)-3-(((2- methoxyethyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (Compound 25) R)OHMe13

[0306] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed benzyl N-([(3R)-3-([8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-yl]aminocyclopentyl]methyl-N-(2-methoxyethyl)carbamate (80 mg, 0.135 mmol, 1.2 equiv), dioxane (2 mL), H2O (0.2 mL), (1R)-N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (49.52 mg, 0.113 mmol, 1.0 equiv), K2CO3(46.81 mg, 0.338 mmol, 3.0 equiv), Pd(dppf)Cl2(4.13 mg, 0.006 mmol, 0.05 equiv). The resulting solution was stirred for 16 h at 100 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.1% FA) and ACN, 20% to 98% gradient in 6 min; detector, UV 254 nm. The collected fractions were combined and concentrated under vacuum. This resulted in benzyl N-([(3R)-3-[(6-(3-[(1R)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl-8-methoxyquinazolin-2-yl)amino]cyclopentyl]methyl-N-(2- methoxyethyl)carbamate (44 mg, 47.40%) as a light yellow solid.

[0307] LCMS of 3: RT = 1.283 min, m / z 822.1 [M+H]+F F OO (R) O O (R)OHMe3

[0308] Into a 8-mL vial was placed benzyl N-([(1R,3R)-3-[(6-(3-[(1R)-6-chloro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl-8-methoxyquinazolin-2- yl)amino]cyclopentyl]methyl-N-(2-methoxyethyl)carbamate (44 mg, 0.054 mmol, 1 equiv), TFA (0.5 mL). The resulting solution was stirred for 2 h at 60 °C. The reaction was concentrated under vacuum. To the above mixture was added MeOH (0.5 mL) and K2CO3 (73.95 mg, 0.540 mmol, 10.0 equiv). The resulting mixture was stirred for additional 1 h at 40 °C. The solid was filtered out. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% NH3H2O) and ACN, 20% to 98% gradient in 6 min; detector, UV 254 nm. Lyophilization. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-([(1R,3R)-3- ([(2-methoxyethyl)amino]methylcyclopentyl]aminoquinazolin-6-yl)phenyl]-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (9.9 mg, 26.64%) as a off-white solid.

[0309] LCMS: RT = 1.027 min, m / z 688.2 [M+H]+

[0310] 1H NMR:1H NMR (300 MHz, CD3OD) δ 9.03 (s, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.41 (d, J = 5.7 Hz, 1H), 7.30 (s, 1H), 7.05 (d, J = 9.7 Hz, 2H), 5.15 (t, J = 6.8 Hz, 1H), 4.61 (s, 1H), 3.99 (s, 3H), 3.61 (t, J = 5.2 Hz, 2H), 3.41 (s, 3H), 3.08 – 2.91 (m, 3H), 2.87 (d, J = 7.4 Hz, 2H), 2.46 (d, J = 8.1 Hz, 2H), 1.86 (dd, J = 16.9, 9.5 Hz, 3H). Example S-9: Synthesis of (R)-6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-(((1R,3R)-3-(((2- methoxyethyl)(methyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 22)OMe OMec

[0311] Into a 250-mL three-necked flask purged and maintained with an inert atmosphere of nitrogen, was placed with a mixture of tert-butyl N-[(1R)-3-[(2- methoxyethyl)carbamoyl]cyclopentyl]carbamate (2 g, 6.984 mmol, 1 equiv), DCM (10 mL). To the above mixture was added DIBAL-H (62.86 mL, 62.856 mmol, 9.0 equiv) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 5 h. To the above mixture was added H2O (2.6 mL), NaOH (15% aq) (2.6 mL) and H2O (6.2 mL). The resulting mixture was stirred for additional 10 min at room temperature. The resulting mixture was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl N-(3-([(2-methoxyethyl)amino]methylcyclopentyl)carbamate (1.66 g, 87.26%) as a off-white solid.

[0312] LCMS of 2: RT = 0.203 min, m / z 273.2 [M+H]+O OMe HCHO, NaBH3CN, AcOH N oc MeOH, r.t, 1 h (R) Boc(R) step2 NH 23

[0313] Into a 50-mL round-bottom flask was placed with a mixture of tert-butyl N-(3- ([(2-methoxyethyl)amino]methylcyclopentyl)carbamate (1.6 g, 5.874 mmol, 1 equiv), MeOH (16 mL), AcOH (0.35 g, 5.874 mmol, 1.0 equiv), HCHO (1.76 g, 17.622 mmol, 3.0 equiv, 30%), NaBH3CN (0.74 g, 11.748 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% NH3H2O) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min; detector, UV 254 nm. The collected fractions were combined and concentrated under vacuum. This resulted in tert-butyl N-(3-([(2- methoxyethyl)(methyl)amino]methylcyclopentyl)carbamate (1.0 g, 59.44%) as a brown viscous oil.

[0314] LCMS of 3: RT = 0.617 min, m / z 287.2 [M+H]+OMe OMe 234

[0315] Into a 50-mL round-bottom flask was placed with a mixture of tert-butyl N-(3- ([(2-methoxyethyl)(methyl)amino]methylcyclopentyl)carbamate (1.0 g, 3.491 mmol, 1 equiv), DCM (10 mL), TFA (3.3 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated under vacuum. This resulted in 3-([(2- methoxyethyl)(methyl)amino]methylcyclopentan-1-amine (900 mg, 83.02%) as a brown viscous oil.

[0316] LCMS of 4: RT = 0.488 min, m / z 187.2 [M+H]+O Br

[0317] Into a 40-mL vial was placed with a mixture of 3-([(2- methoxyethyl)(methyl)amino]methylcyclopentan-1-amine (900 mg, 2.899 mmol, 1.5 equiv, 60%), DMSO (9 mL), 6-bromo-2-chloro-8-methoxyquinazoline (528.52 mg, 1.933 mmol, 1.0 equiv), K2CO3 (2670.64 mg, 19.327 mmol, 10.0 equiv). The reaction mixture was stirred at 130 °C for 4 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.1% FA) and ACN (25% ACN to 25% in 2 min, 25% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min; detector, UV 254 nm. The collected fractions were combined and concentrated under vacuum. This resulted in 6-bromo-8-methoxy-N-(3-([(2- methoxyethyl)(methyl)amino]methylcyclopentyl)quinazolin-2-amine (763 mg, 93.27%) as a brown viscous oil.

[0318] LCMS of 6: RT = 0.822 min, m / z 425.0 [M+H+2]+OMe O O

[0319] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed with a mixture of 6-bromo-8-methoxy-N-(3-([(2- methoxyethyl)(methyl)amino]methylcyclopentyl)quinazolin-2-amine (763 mg, 1.802 mmol, 1 equiv), dioxane (8 mL), KOAc (353.76 mg, 3.604 mmol, 2.0 equiv), bis(pinacolato)diboron (915.34 mg, 3.604 mmol, 2.0 equiv), Pd(dppf)Cl2(65.94 mg, 0.090 mmol, 0.05 equiv). The reaction mixture was stirred at 90 °C for 2 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.1% FA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min; detector, UV 254 nm. The collected fractions were combined and concentrated under vacuum. This resulted in 8-methoxy-N-(3-([(2- methoxyethyl)(methyl)amino]methylcyclopentyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)quinazolin-2-amine (649 mg, 76.55%) as a brown solid.

[0320] LCMS of 8: RT = 0.848 min, m / z 471.2 [M+H]+OM)OH8

[0321] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed with a mixture of 8-methoxy-N-(3-([(2- methoxyethyl)(methyl)amino]methylcyclopentyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)quinazolin-2-amine (75 mg, 0.159 mmol, 1.4 equiv), (1R)-N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (49.96 mg, 0.114mmol, 1.0 equiv), dioxane (0.5 mL), H2O (0.05 mL), K2CO3 (47.22 mg, 0.341 mmol, 3.0 equiv), Pd(dppf)Cl2(4.17 mg, 0.006 mmol, 0.05 equiv). The reaction mixture was stirred at 100 °C for 16 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.1% FA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min; detector, UV 254 nm. Lyophilization. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-([(1R)-3-([(2- methoxyethyl)(methyl)amino]methylcyclopentyl]aminoquinazolin-6-yl)phenyl]-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamide (15.9 mg, 19.88%) as a off-white solid.

[0322] LCMS: RT = 1.093 min, m / z 702.2 [M+H]+

[0323] 1H NMR:1H NMR (300 MHz, CD3OD) δ 9.03 (s, 1H), 7.65 – 7.55 (m, 2H), 7.51 – 7.40 (m, 1H), 7.29 (s, 1H), 7.08 (d, J = 10.1 Hz, 1H), 7.01 (s, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.60 – 4.54 (m, 1H), 3.98 (s, 3H), 3.59 (d, J = 5.7 Hz, 2H), 3.37 (s, 3H), 3.00 – 2.92 (m, 1H), 2.75 (t, J = 5.6 Hz, 2H), 2.57 (d, J = 7.3 Hz, 2H), 2.46 (d, J = 7.9 Hz, 2H), 2.41 (s, 3H), 2.22 (s, 1H), 1.91 (s, 1H), 1.89 – 1.72 (m, 3H), 1.65 (s, 1H), 1.36 (dd, J = 13.0, 8.8 Hz, 1H). Example S-10: Synthesis of 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin- 4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-1-methyl-2,3-dihydro-1H-indene-4- sulfonamide (Compound 19) F e H Br1 2

[0324] Into a 8-mL vial was placed with a mixture of N-(3-bromo-2,4-difluorophenyl)-6- chloro-1-oxo-2,3-dihydroindene-4-sulfonamide (100 mg, 0.229 mmol, 1 equiv), Et2O (1 mL). To the above mixture was added MeMgBr (0.76 mL, 2.290 mmol, 10 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution (2 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na2SO4. After filtration, thefiltrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.1% FA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. The collected fractions were combined and concentrated under vacuum. This resulted in N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-1-methyl-2,3- dihydroindene-4-sulfonamide (87 mg, 83.92%) as a off-white solid.

[0325] LCMS of 2: RT = 0.635 min, m / z 450.0, 452.0 [M-H]- F MeBrOH

[0326] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed with a mixture of N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-1-methyl-2,3- dihydroindene-4-sulfonamide (50 mg, 0.110 mmol, 1 equiv), N-[1-(2- methoxyethyl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- amine (68.31 mg, 0.165 mmol, 1.5 equiv), DMSO (1 mL), H2O (0.1 mL), K2CO3(45.79 mg, 0.330 mmol, 3.0 equiv), RuPhos Palladacycle Gen.3 (4.62 mg, 0.006 mmol, 0.05 equiv). The reaction mixture was stirred at 100 °C for 3 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.1% FA) and ACN (25% ACN to 25% in 2 min, 25% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. Lyophilization. This resulted in 6-chloro-N- [2,4-difluoro-3-(2-([1-(2-methoxyethyl)piperidin-4-yl]aminoquinazolin-6-yl)phenyl]-1- hydroxy-1-methyl-2,3-dihydroindene-4-sulfonamide (24.7 mg, 33.54%) as a white solid.

[0327] LCMS: RT = 1.040 min, m / z 658.2 [M+H]+

[0328] 1H NMR:1H NMR (300 MHz, CD3OD) δ 9.05 (s, 1H), 7.69 (s, 1H), 7.64 – 7.52 (m, 4H), 7.45 (td, J = 8.9, 5.7 Hz, 1H), 7.08 (td, J = 9.2, 1.8 Hz, 1H), 4.09 – 3.96 (m, 1H), 3.60 (t, J = 5.6 Hz, 2H), 3.38 (s, 3H), 3.29 – 3.20 (m, 1H), 3.08 (d, J = 11.5 Hz, 2H), 3.05 – 2.89 (m, 1H), 2.72 (t, J = 5.6 Hz, 2H), 2.40 (t, J = 11.5 Hz, 2H), 2.22 – 2.01 (m, 4H), 1.72 (q, J = 10.5 Hz, 2H), 1.45 (s, 3H).Example S-11: Synthesis of 6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin- 4-yl)amino)quinazolin-6-yl)phenyl)-1-oxo-2,3-dihydro-1H-indene-4-sulfonamide (Compound 20) F BrO1 3

[0329] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed with a mixture of N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-oxo-2,3-dihydroindene- 4-sulfonamide (100 mg, 0.229 mmol, 1 equiv), tert-butyl 4-([6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-yl]aminopiperidine-1-carboxylate (208.12 mg, 0.458 mmol, 2.0 equiv), dioxane (1 mL), H2O (0.1 mL), K2CO3(94.95 mg, 0.687 mmol, 3.0 equiv), Pd(dppf)Cl2 (8.38 mg, 0.011 mmol, 0.05 equiv). The reaction mixture was stirred at 100 °C for 4 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% NH3H2O) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. The collected fractions were combined and concentrated under vacuum. This resulted in tert-butyl 4-((6-[3- (6-chloro-1-oxo-2,3-dihydroindene-4-sulfonamido)-2,6-difluorophenyl]quinazolin-2- ylamino)piperidine-1-carboxylate (149 mg, 95.10%) as a brown solid.

[0330] LCMS of 3: RT = 1.310 min, m / z 684.2 [M+H]+Boc OH Cl H Step2 Cl 34

[0331] Into a 8-mL vial was placed with a mixture of tert-butyl 4-((6-[3-(6-chloro-1-oxo- 2,3-dihydroindene-4-sulfonamido)-2,6-difluorophenyl]quinazolin-2-ylamino)piperidine-1- carboxylate (149 mg, 0.218 mmol, 1 equiv), DCM (1.5 mL), TFA (0.3 mL). The reactionmixture was stirred at room temperature for 1 h. The reaction was concentrated under vacuum. This resulted in 6-chloro-N-(2,4-difluoro-3-[2-(piperidin-4-ylamino)quinazolin-6- yl]phenyl-1-oxo-2,3-dihydroindene-4-sulfonamide (150 mg, 94.34%) as a brown solid.

[0332] LCMS of 4: RT = 0.440 min, m / z 584.4 [M+H]+TFA F O F HN O

[0333] Into a 8-mL vial was placed with a mixture of 6-chloro-N-(2,4-difluoro-3-[2- (piperidin-4-ylamino)quinazolin-6-yl]phenyl-1-oxo-2,3-dihydroindene-4-sulfonamide (70 mg, 0.096 mmol, 1 equiv, 80%), DMF (1 mL), K2CO3(39.75 mg, 0.288 mmol, 3.0 equiv), ethane, 1-chloro-2-methoxy- (18.13 mg, 0.192 mmol, 2.0 equiv). The reaction mixture was stirred at 70 °C for 16 h. The solid was filtered out. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.1% TFA) and ACN (25% ACN to 25% in 2 min, 25% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min); detector, UV 254 nm. Lyophilization. This resulted in 6- chloro-N-[2,4-difluoro-3-(2-([1-(2-methoxyethyl)piperidin-4-yl]aminoquinazolin-6- yl)phenyl]-1-oxo-2,3-dihydroindene-4-sulfonamide (15.7 mg, 25.24%) as a brown yellow solid.

[0334] LCMS: RT = 1.040 min, m / z 642.2 [M+H]+

[0335] 1H NMR:1H NMR (300 MHz, CD3OD) δ 9.14 (s, 1H), 7.94 – 7.91 (m, 2H), 7.75 (s, 1H), 7.65 – 7.53 (m, 3H), 7.33 – 7.16 (m, 2H), 4.30 (s, 1H), 3.77 (t, J = 5.0 Hz, 4H), 3.46 (s, 3H), 3.40 (d, J = 4.8 Hz, 4H), 3.26 (d, J = 11.8 Hz, 2H), 2.77 – 2.73 (m, 2H), 2.43 (d, J = 14.2 Hz, 1H), 2.26 (s, 1H), 1.93 (d, J = 13.2 Hz, 2H). Example S-12: Synthesis of (R)-6-chloro-N-(2,4-difluoro-3-(2-((1-(2- hydroxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (Compound 10)F F OO(R) TBSOO O(R) HNOH

[0336] Into a 8-mL vial, was placed (1R)-6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4- ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (100 mg, 0.171 mmol, 1 equiv), (2-bromoethoxy)(tert-butyl)dimethylsilane (81.64 mg, 0.342 mmol, 2.0 equiv), DMF (1 mL), K2CO3 (70.75 mg, 0.513 mmol, 3.0 equiv). The resulting solution was stirred for 2 h at 40 °C. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. This resulted in (1R)-N-(3-{2- [(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}piperidin-4-yl)amino]quinazolin-6-yl}-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (60 mg, 47.24%) as a light yellow solid.

[0337] LCMS: m / z 744.3 [M+H]+FTBSFF34

[0338] Into a 8-mL vial was placed (1R)-N-(3-{2-[(1-{2-[(tert- butyldimethylsilyl)oxy]ethyl}piperidin-4-yl)amino]quinazolin-6-yl}-2,4-difluorophenyl)-6- chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (50 mg, 0.067 mmol, 1 equiv), TFA (0.5 mL, 6.732 mmol, 100.22 equiv). The resulting solution was stirred for 2 h at rt. The resulting mixture was concentrated under vacuum. To afford (1R)-6-chloro-4-{[2,4-difluoro- 3-(2-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]sulfamoyl}-2,3- dihydro-1H-inden-1-yl 2,2,2-trifluoroacetate (60 mg, crude) as a light yellow solid.

[0339] LCMS: m / z 726.1 [M+H]+F O F OO(R) FO O(R)HOH OH4

[0340] Into a 8-mL vial was placed (1R)-6-chloro-4-{[2,4-difluoro-3-(2-{[1-(2- hydroxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]sulfamoyl}-2,3-dihydro-1H- inden-1-yl 2,2,2-trifluoroacetate (60 mg, 0.083 mmol, 1 equiv), K2CO3 (34.26 mg, 0.249 mmol, 3.0 equiv), MeOH (0.6 mL). The resulting solution was stirred for 0.5 h at rt. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(2- {[1-(2-hydroxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide (15.9 mg, 30.48%) as a off white solid.

[0341] LCMS: RT = 0.954 min, m / z 630.2 [M+H]+

[0342] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 7.69 (s, 1H), 7.64 – 7.54 (m, 4H), 7.44 (td, J = 8.8, 5.6 Hz, 1H), 7.12 – 7.03 (m, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.04 (s, 1H), 3.75 (t, J = 6.0 Hz, 2H), 3.26 (ddd, J = 17.4, 8.7, 4.1 Hz, 1H), 3.10 (d, J = 11.8 Hz, 2H), 2.95 (dt, J = 16.9, 8.0 Hz, 1H), 2.68 (t, J = 6.1 Hz, 2H), 2.51 – 2.37 (m, 3H), 2.13 (d, J = 12.4 Hz, 2H), 1.89 (dq, J = 14.7, 7.8 Hz, 1H), 1.76 (d, J = 9.9 Hz, 1H), 1.70 (d, J = 11.0 Hz, 1H). Example S-13: Synthesis of (1R)-6-chloro-N-(2,4-difluoro-3-(2-((1-(1-methoxypropan-2- yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 9)OH DCM, 0oC - r.t, 2 h O O step1 12

[0343] Into a 40 mL vial with an inert atmosphere of nitrogen were added methoxyisopropanol (800 mg, 8.877 mmol, 1 equiv), Et3N (2694.83 mg, 26.631 mmol, 3equiv), DCM and then Ms-Cl (1321.78 mg, 11.540 mmol, 1.3 equiv). The resulting solution was stirred for 2 h at 0 °C. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried with Na2SO4. The mixture was concentrated under vacuum pressure to afford 1-methoxypropan-2- yl methanesulfonate (600 mg, 40.18%) as a colorless oil. F O ) OH O

[0344] Into a 8 mL vial were added 1-methoxypropan-2-yl methanesulfonate (38.75 mg, 0.231 mmol, 1.5 equiv), (1R)-6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4- ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (90 mg, 0.154 mmol, 1.00 equiv), K2CO3(63.67 mg, 0.462 mmol, 3 equiv). The resulting solution was stirred for 16 h at 70 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Water (0.05% NH3H2O) and ACN, 20% to 98% gradient in 6 min; detector, UV 254 nm. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(1-methoxypropan-2-yl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (10.2 mg , 7.91%) as a off white solid.

[0345] LCMS: RT = 1.091 min, m / z 658.0 [M+H]+

[0346] 1H NMR: 1H NMR (400 MHz, Methanol-d4) δ 9.06 (s, 1H), 7.70 (s, 1H), 7.65 – 7.54 (m, 4H), 7.43 (td, J = 8.8, 5.6 Hz, 1H), 7.11 – 7.01 (m, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.03 (dd, J = 12.7, 8.8 Hz, 1H), 3.57 (dd, J = 10.1, 5.8 Hz, 1H), 3.50 – 3.37 (m, 1H), 3.39 (s, 3H), 3.32 – 3.21 (m, 1H), 3.07 (d, J = 11.7 Hz, 2H), 3.02 – 2.89 (m, 2H), 2.68 (t, J = 11.5 Hz, 2H), 2.52 – 2.39 (m, 1H), 2.15 (d, J = 13.0 Hz, 2H), 1.98 – 1.82 (m, 1H), 1.72 (t, J = 11.3 Hz, 2H), 1.18 (d, J = 6.7 Hz, 3H).Example S-14: Synthesis of (1R)-6-chloro-N-(2,4-difluoro-3-(2-((1-(2- methoxypropyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide (Compound 7) EtNO O3 , MSCI

[0347] Into a 40 ml vial were added 2-methoxypropanol (500 mg, 5.548 mmol, 1 equiv), DCM (5 mL), Et3N (1684.27 mg, 16.644 mmol, 3.0 equiv), the temperature of the external bath was carefully maintained 0oC during the addition, addded methanesulfonyl chloride (826.11 mg, 7.212 mmol, 1.3 equiv). The resulting solution was stirred for 2 h at rt. The resulting solution was extracted with 3x10 mL of DCM. The organic layers were combined, washed with saturated sodium carbonate and brine, dried with Na2SO4and concentrated under vacuum. The resulted in 2-methoxypropyl methanesulfonate (890 mg, crude) as a light yellow liquid.

[0348] LCMS: m / z 168.2 [M+H]+) OHO2

[0349] Into a 8 ml vial was placed was placed (1R)-6-chloro-N-{2,4-difluoro-3-[2- (piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (50 mg, 0.085 mmol, 1.00 equiv), DMF (0.5 mL), K2CO3 (35.37 mg, 0.255 mmol, 3.0 equiv), 2-methoxypropyl methanesulfonate (86.11 mg, 0.510 mmol, 6.0 equiv). The resulting solution was stirred for 5 h at 70 °C. The solids were filtered out. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min;Detector, UV 220nm. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(2- methoxypropyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (9.7 mg, 16.50%) as a off white solid.

[0350] LCMS: RT = 1.149 min, m / z 658.2 [M+H]+

[0351] 1H NMR:1H NMR (400 MHz, Methanol-d4) δ 9.05 (s, 1H), 7.71 (s, 1H), 7.66 – 7.61 (m, 2H), 7.57 (d, J = 10.3 Hz, 2H), 7.39 (td, J = 8.9, 5.7 Hz, 1H), 7.01 (t, J = 9.1 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.06 – 3.96 (m, 1H), 3.39 (s, 3H), 3.06 (s, 1H), 3.03 (s, 1H), 2.97 (dt, J = 16.8, 8.0 Hz, 1H), 2.57 (dd, J = 13.2, 7.9 Hz, 1H), 2.47 (dd, J = 12.6, 7.7 Hz, 1H), 2.45 – 2.37 (m, 1H), 2.35 (t, J = 11.0 Hz, 2H), 2.08 (s, 1H), 1.89 (dq, J = 14.5, 7.9 Hz, 1H), 1.73 (q, J = 11.3, 10.1 Hz, 2H), 1.31 (s, 1H), 1.17 (d, J = 6.2 Hz, 3H). Example S-15: Synthesis of (1R)-6-chloro-N-(2,4-difluoro-3-(2-((1-(tetrahydrofuran-3- yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 11) ) HNOH

[0352] Into a 8 ml vial was placed (1R)-6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4- ylamino) quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (60 mg, 0.102 mmol, 1 equiv), MeOH (0.6 mL), dihydrofuran-3-one (17.63 mg, 0.204 mmol, 2.0 equiv), NaBH3CN (12.87 mg, 0.204 mmol, 2.0 equiv). The resulting solution was stirred for 2 h at 60 °C. The solids were filtered out. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. This resulted in (1R)-6-chloro- N-[2,4-difluoro-3-(2-{[1-(oxolan-3-yl)piperidin-4-yl]amino}quinazolin-6-yl) phenyl]-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (22.2 mg, 32.75%) as a off white solid.

[0353] LCMS: RT = 1.054 min, m / z 656.3 [M+H]+

[0354] 1H NMR: 1H NMR (400 MHz, CD3OD) δ 9.05 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 8.7 Hz, 4H), 7.52 – 7.41 (m, 1H), 7.10 (t, J = 9.1 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.06 – 3.89 (m, 2H), 3.80 (q, J = 8.1 Hz, 1H), 3.74 – 3.65 (m, 1H), 3.29 – 3.18 (m, 1H), 3.14 – 3.04 (m, 2H), 2.95 (dd, J = 17.1, 8.6 Hz, 1H), 2.89 (d, J = 9.8 Hz, 1H), 2.52 – 2.30 (m, 3H), 2.21 – 2.10 (m, 1H), 1.98 – 1.82 (m, 2H), 1.71 (t, J = 12.1 Hz, 2H). Example S-16: (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[1-(pyridin-2- yl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 1) N Br Cl1 3

[0355] Into a 8 mL vial were added 6-bromo-2-chloro-8-methoxyquinazoline (100 mg, 0.366 mmol, 1 equiv), 1-(pyridin-2-yl)piperidin-4-amine (97.21 mg, 0.549 mmol, 1.5 equiv), DIEA (283.53 mg, 2.196 mmol, 6.0 equiv) and DMSO (1 mL) for 2 h at 130oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. This resulted in 6-bromo-8-methoxy-N-[1-(pyridin-2-yl)piperidin-4-yl]quinazolin-2- amine (130 mg, 85.82%) as a light yellow solid.

[0356] LCMS: m / z 414.3 [M+H]+3 5

[0357] Into a 8 mL vial and maintained with an inert atmosphere of nitrogen, were added 6-bromo-8-methoxy-N-[1-(pyridin-2-yl)piperidin-4-yl]quinazolin-2-amine (120 mg, 0.290 mmol, 1 equiv), bis(pinacolato)diboron (110.33 mg, 0.435 mmol, 1.5 equiv), KOAc (56.85 mg, 0.580 mmol, 2.0 equiv), dioxane (1.2 mL), Pd2(dba)3 (13.26 mg, 0.014 mmol, 0.05 equiv) and Sphos (11.89 mg, 0.029 mmol, 0.1 equiv). The resulting solution was stirred for 16 h at 90oC. The product was used in the next step directly without further purification.

[0358] LCMS : m / z 461.3 [M+H]+F ) OH

[0359] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 8-methoxy-N-[1-(pyridin-2-yl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-amine (100 mg, 0.217 mmol, 1 equiv), (1R)-N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (95.08 mg, 0.217 mmol, 1 equiv), K2CO3 (89.87 mg, 0.651 mmol, 3.0 equiv), dioxane (1 mL), H2O (0.1 mL), Pd(dppf)Cl2 (7.93 mg, 0.011 mmol, 0.05 equiv). The resulting solution was stirred for 16 h at 100 ℃. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). Lyophilization. To afford (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[1-(pyridin-2-yl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (41.5 mg, 26.83%) as a off-white solid.

[0360] LCMS: RT = 2.895 min, m / z 693.3 [M+H]+

[0361] 1H NMR:1H NMR (400 MHz, Methanol-d4) δ 9.05 (s, 1H), 8.13 – 8.06 (m, 1H), 7.64 – 7.54 (m, 3H), 7.49 (td, J = 8.8, 5.7 Hz, 1H), 7.28 (s, 1H), 7.12 (td, J = 9.1, 1.7 Hz, 1H), 7.00 (d, J = 1.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.71 – 6.63 (m, 1H), 5.15 (t, J = 6.8 Hz,1H), 4.28 (d, J = 13.4 Hz, 2H), 3.99 (s, 3H), 3.24 (ddd, J = 17.5, 8.6, 3.8 Hz, 1H), 3.19 – 3.08 (m, 2H), 2.95 (dt, J = 17.0, 8.0 Hz, 1H), 2.46 (dtd, J = 15.2, 7.7, 3.9 Hz, 1H), 2.16 (d, J = 12.3 Hz, 2H), 1.95 – 1.81 (m, 1H), 1.64 (qd, J = 12.0, 3.9 Hz, 2H). Example S-17: (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[1-(pyridin-3- yl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 2) N Br Cl

[0362] Into a 8 mL vial were added 6-bromo-2-chloro-8-methoxyquinazoline (100 mg, 0.366 mmol, 1 equiv), 1-(pyridin-3-yl)piperidin-4-amine (97.21 mg, 0.549 mmol, 1.5 equiv), DIEA (283.53 mg, 2.196 mmol, 6.0 equiv) and DMSO (1 mL) for 2 h at 130oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. This resulted in 6-bromo-8-methoxy-N-[1-(pyridin-3-yl)piperidin-4-yl]quinazolin-2- amine (110 mg, 72.62%) as a light yellow solid.

[0363] LCMS: m / z 414.3 [M+H]+N3 5

[0364] Into a 8 mL vial and maintained with an inert atmosphere of nitrogen, were added 6-bromo-8-methoxy-N-[1-(pyridin-3-yl)piperidin-4-yl]quinazolin-2-amine (100 mg, 0.241 mmol, 1 equiv), bis(pinacolato)diboron (91.94 mg, 0.361 mmol, 1.5 equiv), KOAc (47.38 mg, 0.482 mmol, 2.0 equiv), dioxane (1 mL), Pd2(dba)3 (11.05 mg, 0.012 mmol, 0.05 equiv) and Sphos (9.91 mg, 0.024 mmol, 0.1 equiv), The resulting solution was stirred for 16 h at 90oC. The product was used in the next step directly without further purification.

[0365] LCMS: m / z 461.3 [M+H]+F N ) OH

[0366] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 8-methoxy-N-[1-(pyridin-3-yl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-amine (70 mg, 0.152 mmol, 1 equiv), (1R)-N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (66.56 mg, 0.152 mmol, 1 equiv), K2CO3(62.91 mg, 0.456 mmol, 3.0 equiv), dioxane (1 mL), H2O (0.1 mL), Pd(dppf)Cl2 (5.55 mg, 0.008 mmol, 0.05 equiv). The resulting solution was stirred for 16 h at 100 ℃. The crude product was purified by Prep-HPLC with the following conditions (Prep- HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). Lyophilization. To afford (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[1-(pyridin-3-yl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (10.6 mg, 9.88%) as an off-white solid.

[0367] LCMS: RT = 1.129 min, m / z 693.2 [M+H]+

[0368] 1H NMR:1H NMR (400 MHz,CD3OD) δ 9.06 (s, 1H), 8.29 (d, J = 2.9 Hz, 1H), 7.97 (dd, J = 4.6, 1.3 Hz, 1H), 7.60 (s, 2H), 7.53 – 7.43 (m, 2H), 7.33 – 7.28 (m, 2H), 7.16 – 7.07 (m, 1H), 7.01 (s, 1H), 5.15 (t, J = 6.9 Hz, 1H), 4.29 (s, 1H), 3.99 (s, 3H), 3.83 (d, J = 12.7 Hz, 2H), 3.23 (dt, J = 8.6, 4.5 Hz, 1H), 3.06 (t, J = 11.9 Hz, 2H), 2.95 (dt, J = 16.7, 8.0Hz, 1H), 2.46 (td, J = 12.2, 11.7, 7.6 Hz, 1H), 2.25 – 2.17 (m, 2H), 1.95 – 1.83 (m, 1H), 1.86 – 1.70 (m, 2H). Example S-18: (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[1-(pyridin-4- yl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 3) N Br Cl1 3

[0369] Into a 8-mL vial was placed 6-bromo-2-chloro-8-methoxyquinazoline (100 mg, 0.366 mmol, 1 equiv), 1-(pyridin-4-yl)piperidin-4-amine (97.21 mg, 0.549 mmol, 1.5 equiv), K2CO3(151.59 mg, 1.098 mmol, 3.0 equiv), DMSO (1 mL). The resulting solution was stirred for 4 h at 130 °C. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. This resulted in 6-bromo-8- methoxy-N-[1-(pyridin-4-yl)piperidin-4-yl]quinazolin-2-amine (80 mg, 52.81%) as a light yellow solid.

[0370] LCMS: RT = 0.758 min, m / z 414.0 [M+H]+N3 5

[0371] Into a 8 ml vial and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-8-methoxy-N-[1-(pyridin-4-yl)piperidin-4-yl]quinazolin-2-amine (70 mg,0.169 mmol, 1 equiv), bis(pinacolato)diboron (64.36 mg, 0.254 mmol, 1.5 equiv), KOAc (33.16 mg, 0.338 mmol, 2.0 equiv), dioxane (1 mL), Pd2(dba)3(7.74 mg, 0.008 mmol, 0.05 equiv), Sphos (6.94 mg, 0.017 mmol, 0.1 equiv). The reaction mixture was stirred at 90 °C for 2 h. The product was used in the next step directly without further purification.

[0372] LCMS: m / z 461.3 [M+H]+F O N ) OH

[0373] Into a 8 ml vial and maintained with an inert atmosphere of nitrogen, was placed 8-methoxy-N-[1-(pyridin-4-yl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-amine (30 mg, 0.065 mmol, 1 equiv), (1R)-N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (37.08 mg, 0.085 mmol, 1.3 equiv), K2CO3(26.96 mg, 0.195 mmol, 3.0 equiv), dioxane (0.3 mL), H2O (0.03 mL), Pd(dppf)Cl2 (2.38 mg, 0.003 mmol, 0.05 equiv). The reaction mixture was stirred for 16 h at 100oC. The reaction mixture was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). Lyophilization. To afford (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[1-(pyridin-4- yl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (2.3 mg, 4.74%) as an off white solid.

[0374] LCMS: RT = 1.150 min, m / z 693.2 [M+H]+

[0375] 1H NMR:1H NMR (400 MHz,CD3OD) δ 9.05 (s, 1H), 8.12 (d, J = 6.0 Hz, 2H), 7.64 – 7.57 (m, 2H), 7.51 – 7.40 (m, 1H), 7.30 (s, 1H), 7.13 – 7.00 (m, 2H), 6.94 (d, J = 6.3 Hz, 2H), 5.15 (t, J = 6.8 Hz, 1H), 4.40 (s, 1H), 4.10 (d, J = 13.6 Hz, 2H), 3.99 (s, 3H), 3.66 – 3.58 (m, 0H), 3.23 (t, J = 12.5 Hz, 3H), 2.96 (dt, J = 16.9, 8.0 Hz, 1H), 2.46 (d, J = 9.0 Hz, 1H), 2.20 (d, J = 13.1 Hz, 2H), 1.89 (dt, J = 12.9, 7.2 Hz, 1H), 1.67 (q, J = 11.4 Hz, 2H), 1.31 (s, 1H).Example S-19: (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(pyridin-2-yl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 4) Br N Br1 3

[0376] Into a 8 mL vial was placed 1-(pyridin-2-yl)piperidin-4-amine (200 mg, 1.128 mmol, 1 equiv), 6-bromo-2-chloroquinazoline (412.11 mg, 1.692 mmol, 1.5 equiv), DIEA (437.51 mg, 3.384 mmol, 3 equiv), DMSO(2mL). The resulting solution was stirred for 2 hours at 130 ℃, The reaction was then quenched by the addition of 5 mL H2O. The resulting solution was extracted with 3x5 mL of EA. The resulting mixture was washed with 1 x10 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The result in6-bromo-N-[1-(pyridin-2-yl)piperidin-4-yl]quinazolin-2-amine (130 mg, 29.98%) as white solid.

[0377] LCMS: RT = 0.406 min, m / z 386.3 [M+H]+H step2 H 34

[0378] Into a 8 mL vial with an inert atmosphere of nitrogen was placed 6-bromo-N-[1- (pyridin-2-yl)piperidin-4-yl]quinazolin-2-amine (1120 mg, 2.915 mmol, 1 equiv), bis(pinacolato)diboron (1110.18 mg, 4.373 mmol, 1.5 equiv), Pd(dppf)Cl2 (213.26 mg, 0.292 mmol, 0.1 equiv), KOAc (858.11 mg, 8.745 mmol, 3 equiv), dioxane(1mL). The resultingsolution was stirred for 2 hours at 90oC. The product was used in the next step directly without further purification. This resulted in N-[1-(pyridin-2-yl)piperidin-4-yl]-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine 62% in LCMS.

[0379] LCMS: RT = 1.021 min, m / z 432.2 [M+H]+F O ) OH

[0380] Into a 8 mL vial with an inert atmosphere of nitrogen was placed N-[1-(pyridin-2- yl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (120 mg, 0.278 mmol, 1 equiv), (1R)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (122.04 mg, 0.278 mmol, 1 equiv), Pd(dppf)Cl2 (20.36 mg, 0.028 mmol, 0.1 equiv), K2CO3 (115.34 mg, 0.834 mmol, 3 equiv), H2O（0.1mL）. The resulting solution was stirred for 2 hours at 100oC. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and CH3CN (16% CH3CN up to 34% in 10 min); Detector, UV 220&254 nm. Lyophilization. This resulted in (1R)-6-chloro- N-[2,4-difluoro-3-(2-{[1-(pyridin-2-yl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (50.4 mg, 27.32%) as a off white solid.

[0381] LCMS: RT = 1.274 min, m / z 663.2 [M+H]+

[0382] 1H NMR: 1H NMR (300 MHz, Methanol-d4) δ 9.06 (s, 1H), 8.10 (dd, J = 5.1, 2.0 Hz, 1H), 7.69 (s, 1H), 7.64 – 7.52 (m, 5H), 7.47 (td, J = 8.9, 5.7 Hz, 1H), 7.11 (td, J = 9.1, 1.8 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.66 (dd, J = 7.1, 5.0 Hz, 1H), 5.15 (t, J = 6.7 Hz, 1H), 4.28 (t, J = 8.9 Hz, 3H), 3.24 (ddd, J = 17.4, 8.6, 4.0 Hz, 1H), 3.12 (t, J = 12.4 Hz, 2H), 3.03 – 2.86 (m, 1H), 2.54 – 2.37 (m, 1H), 2.17 (d, J = 12.7 Hz, 2H), 1.89 (dq, J = 14.7, 7.8 Hz, 1H), 1.66 (qd, J = 11.9, 3.9 Hz, 2H)Example S-20: ((1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(pyridin-3-yl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 5) Br N N Br

[0383] Into a 8 mL vial was placed 1-(pyridin-3-yl)piperidin-4-amine (150 mg, 0.846 mmol, 1 equiv), 6-bromo-2-chloroquinazoline (309.08 mg, 1.269 mmol, 1.5 equiv), DIEA (328.13 mg, 2.538 mmol, 3 equiv). The resulting solution was stirred for 2 hour at 130 ℃. The reaction was then quenched by the addition of 5 mL H2O. The resulting solution was extracted with 3x5 mL of EA. The resulting mixture was washed with 1 x10 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The result in 6-bromo-N- [1-(pyridin-3-yl)piperidin-4-yl]quinazolin-2-amine (85 mg, 26.14%) as white solid.

[0384] LCMS: RT = 0.421 min, m / z 386.4 [M+H]+34

[0385] Into a 8 mL vial with an inert atmosphere of nitrogen was placed 6-bromo-N-[1- (pyridin-3-yl)piperidin-4-yl]quinazolin-2-amine (90 mg, 0.234 mmol, 1 equiv), bis(pinacolato)diboron (89.21 mg, 0.351 mmol, 1.5 equiv), Pd(dppf)Cl2(17.14 mg, 0.023 mmol, 0.1 equiv), KOAc (68.96 mg, 0.702 mmol, 3 equiv), dioxane(1mL). The resulting solution was stirred for 2 hour at 90oC. The product was used in the next step directly without further purification. This resulted in N-[1-(pyridin-3-yl)piperidin-4-yl]-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine) 46% in LCMS.

[0386] LCMS: RT=1.006 min, m / z 432.2[M+H]+ F OO(R) N ) OH

[0387] Into a 8 mL vial with an inert atmosphere of nitrogen was placed N-[1-(pyridin-3- yl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (80 mg, 0.185 mmol, 1 equiv), (1R)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide(81.36 mg, 0.185 mmol, 1 equiv), Pd(dppf)Cl2(13.57 mg, 0.018 mmol, 0.1 equiv), K2CO3 (76.90 mg, 0.555 mmol, 3 equiv), H2O（0.1mL）, The resulting solution was stirred for 2 hour at 100oC. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and CH3CN (16% CH3CN up to 34% in 10 min); Detector, UV 220&254 nm. Lyophilization. This resulted in ((1R)-6-chloro- N-[2,4-difluoro-3-(2-{[1-(pyridin-3-yl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (8.2 mg, 6.67%)as a off white solid.

[0388] LCMS: RT = 1.513 min, m / z 663.2 [M+H]+

[0389] 1H NMR: 1H NMR (300 MHz, Methanol-d4) δ 9.07 (s, 1H), 8.29 (d, J = 3.0 Hz, 1H), 8.01 – 7.93 (m, 1H), 7.70 (s, 1H), 7.61 (d, J = 2.7 Hz, 4H), 7.52 – 7.38 (m, 2H), 7.30 (dd, J = 8.5, 4.7 Hz, 1H), 7.09 (t, J = 9.2 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.57 (s, 0H), 4.20 (s, 1H), 3.84 (d, J = 12.9 Hz, 3H), 3.31 – 3.18 (m, 1H), 3.08 – 2.86 (m, 3H), 2.45 (d, J = 7.3 Hz, 1H), 2.22 (d, J = 12.7 Hz, 2H), 1.89 (dd, J = 14.1, 7.0 Hz, 1H), 1.78 (d, J = 11.0 Hz, 2H), 1.31 (s, 1H) Example S-21: (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(pyridin-4-yl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 6)Br N N Br1 3

[0390] Into a 8 mL vial was placed 1-(pyridin-4-yl)piperidin-4-amine (150 mg, 0.846 mmol, 1 equiv), 6-bromo-2-chloroquinazoline (309.08 mg, 1.269 mmol, 1.5 equiv), DIEA (328.13 mg, 2.538 mmol, 3 equiv). The resulting solution was stirred for 2 hour at 130℃. The reaction was then quenched by the addition of 5 mL H2O. The resulting solution was extracted with 3x5 mL of EA. The resulting mixture was washed with 1 x10 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The result in 6-bromo-N- [1-(pyridin-4-yl)piperidin-4-yl]quinazolin-2-amine (100 mg, 30.75%) as white solid.

[0391] LCMS:m / z 384 [M+H]+N34

[0392] Into a 8 mL vial with an inert atmosphere of nitrogen was placed 6-bromo-N-[1- (pyridin-3-yl)piperidin-4-yl]quinazolin-2-amine (90 mg, 0.234 mmol, 1 equiv), bis(pinacolato)diboron (89.21 mg, 0.351 mmol, 1.5 equiv), Pd(dppf)Cl2 (17.14 mg, 0.023 mmol, 0.1 equiv), KOAc (68.96 mg, 0.702 mmol, 3 equiv), dioxane(1mL). The resulting solution was stirred for 2 hour at 90oC. The product was used in the next step directly without further purification. This resulted in N-[1-(pyridin-3-yl)piperidin-4-yl]-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine) 46% in LCMS.

[0393] Into a 8 mL vial with an inert atmosphere of nitrogen was placed 6-bromo-N-[1- (pyridin-4-yl)piperidin-4-yl]quinazolin-2-amine (80 mg, 0.208 mmol, 1 equiv), bis(pinacolato)diboron (1.5 equiv), Pd(dppf)Cl2 (15.23 mg, 0.021 mmol, 0.1 equiv), KOAc(61.29 mg, 0.624 mmol, 3 equiv), dioxane(1mL). The resulting solution was stirred for 2 hour at 90oC. The product was used in the next step directly without further purification. This resulted in N-[1-(pyridin-4-yl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-amine 65% in LCMS.

[0394] LCMS: RT = 0.464 min m / z 432.4 [M+H]+

[0395] Into a 8 mL vial with an inert atmosphere of nitrogen was placed N-[1-(pyridin-4- yl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (80 mg, 0.185 mmol, 1 equiv), (1R)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (89.49 mg, 0.204 mmol, 1.1 equiv), Pd(dppf)Cl2(13.57 mg, 0.018 mmol, 0.1 equiv), K2CO3 (76.90 mg, 0.555 mmol, 3 equiv), H2O（0.1mL）. The resulting solution was stirred for 2 hours at 100oC. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and CH3CN (16% CH3CN up to 34% in 10 min); Detector, UV 220&254 nm. Lyophilization. This resulted in (1R)-6-chloro- N-[2,4-difluoro-3-(2-{[1-(pyridin-4-yl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (4.1 mg, 3.33%) as a off white solid.

[0396] LCMS: RT = 3.392 min, m / z 663.2 [M+H]+

[0397] 1H NMR: 1H NMR (300 MHz, Methanol-d4) δ 9.07 (s, 1H), 8.12 (d, J = 6.1 Hz, 2H), 7.71 (s, 1H), 7.65 – 7.55 (m, 4H), 7.49 – 7.35 (m, 1H), 7.05 (t, J = 9.2 Hz, 1H), 6.92 (d, J = 6.4 Hz, 2H), 5.15 (t, J = 6.8 Hz, 1H), 4.58 (s, 1H), 4.09 (d, J = 13.3 Hz, 2H), 3.30 – 3.13 (m, 2H), 2.96 (dt, J = 17.1, 8.0 Hz, 1H), 2.44 (s, 1H), 2.20 (d, J = 12.9 Hz, 2H), 1.89 (dd, J = 13.1, 6.9 Hz, 1H), 1.70 (dd, J = 12.7, 9.0 Hz, 2H), 1.31 (s, 1H). Example S-22: (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(2-methoxycyclopentyl)piperidin- 4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 8)F H h

[0398] Into a 8 ml vial was placed (1R)-6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4- ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (60 mg, 0.102 mmol, 1 equiv), MeOH (0.6 mL), 2-methoxycyclopentan-1-one (23.37 mg, 0.204 mmol, 2.0 equiv), NaBH3CN (12.87 mg, 0.204 mmol, 2.0 equiv). The resulting solution was stirred for 2 h at 60 °C. The solids were filtered out. The crude product was purified by Prep- HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(2-methoxycyclopentyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (11 mg, 14.92%) as a off white solid.

[0399] LCMS: RT = 2.403 min, m / z 684.2 [M+H]+

[0400] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 7.69 (s, 1H), 7.64 – 7.54 (m, 4H), 7.50 – 7.40 (m, 1H), 7.08 (t, J = 9.0 Hz, 1H), 5.15 (t, J = 6.7 Hz, 1H), 4.04 (s, 1H), 3.76 (s, 1H), 3.25 (td, J = 8.6, 3.9 Hz, 1H), 3.19 (s, 1H), 3.16 (s, 1H), 3.09 (d, J = 11.8 Hz, 1H), 2.95 (dt, J = 17.0, 8.0 Hz, 1H), 2.71 – 2.64 (m, 1H), 2.41 (q, J = 12.2, 11.5 Hz, 4H), 2.14 (d, J = 12.6 Hz, 2H), 2.02 (s, 1H), 1.88 (dq, J = 22.4, 7.2 Hz, 2H), 1.72 (s, 5H), 1.69 (s, 1H), 1.58 – 1.46 (m, 1H).Example S-23: (1R)-6-chloro-N-(2,4-difluoro-3-{2-[(1-propylpiperidin-4- yl)amino]quinazolin-6-yl}phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 12) F F OORO OR) HN OH1

[0401] Into a 8 mL vial was placed (1R)-6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4- ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (65 mg, 0.111 mmol, 1 equiv), propionaldehyde (9.66 mg, 0.167 mmol, 1.5 equiv), NaBH3CN (13.94 mg, 0.222 mmol, 2 equiv), MeOH(1mL). The resulting solution was stirred for 2 hours at RT. The crude product (3 mL) was purified by Prep-HPLC with the following conditions(2#- analyse-HPLC-SHIMADZU(HPLC-01)): Column, XBridge prep OBD 19*150mm 5um C- 01; mobile phase, Water(0.1% NH3.H2O ) and ACN( ACN 30% up to 50% in 7 min); Detector, UV 254 &220 nm, lyophilization. The result in (1R)-6-chloro-N-(2,4-difluoro-3- {2-[(1-propylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (3.2 mg, 4.59%) as off-white solid.

[0402] LCMS: RT = 2.618 min, m / z 628.3 [M+H]+

[0403] 1H NMR : 1H NMR (300 MHz, Methanol-d4) δ 9.10 (s, 1H), 7.72 (s, 1H), 7.61 (d, J = 2.5 Hz, 2H), 7.50 – 7.39 (m, 1H), 7.12 (t, J = 8.8 Hz, 2H), 5.16 (t, J = 6.7 Hz, 2H), 4.57 (s, 1H), 4.24 (s, 1H), 3.48 (s, 1H), 3.00 – 2.89 (m, 3H), 2.31 (s, 1H), 1.91 (d, J = 6.7 Hz, 2H), 1.77 (d, J = 8.4 Hz, 2H), 1.31 (s, 1H), 1.05 (t, J = 7.4 Hz, 3H). Example S-24: Synthesis of (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[(1R)-3- [(methylamino)methyl]cyclopentyl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (Compound 13)O NH2O R R cHOp 12

[0404] Into a 50 mL round-bottom flask were added (1R,3R)-3-[(tert- butoxycarbonyl)amino]cyclopentane-1-carboxylic acid (800 mg, 3.489 mmol, 1 equiv), methylamine (162.55 mg, 5.233 mmol, 1.5 equiv), DIEA (1352.92 mg, 10.467 mmol, 3.0 equiv), HATU (1592.08 mg, 4.187 mmol, 1.2 equiv), DMF (8 mL) for 2 h at rt. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. This resulted in tert-butyl N-[(1R,3R)-3-(methylcarbamoyl)cyclopentyl]carbamate (820 mg, 96.98%) as a brown yellow solid.

[0405] LCMS: m / z 242.3 [M+H]+cstep2 2 3

[0406] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[(1R,3R)-3-(methylcarbamoyl)cyclopentyl]carbamate (770 mg, 3.178 mmol, 1 equiv), DCM (7.7 mL), The temperature of the external bath was carefully maintained between 0 and 10 degrees C during the addition. Then added DIBAL-H (4067.36 mg, 28.602 mmol, 9.0 equiv). The resulting solution was stirred for 2h at 0 °C. The reaction was then quenched by the addition of 20mL of water / ice and 8 mL 15% sodium hydroxide solution. The resulting was dried bysodiumsulphate. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. This resulted in tert-butyl N-[(1R,3R)-3- [(methylamino)methyl]cyclopentyl]carbamate (800 mg, crude) as a off white solid.

[0407] LCMS: m / z 228.3 [M+H]+CbzCl, Et3N (R) Boc

[0408] Into a 40 mL vial tert-butyl N-[(1R,3R)-3- [(methylamino)methyl]cyclopentyl]carbamate (800 mg, 3.504 mmol, 1 equiv) , DCM (8 mL), Et3N (1063.62 mg, 10.512 mmol, 3.0 equiv). The temperature of the external bath was carefully maintained between 0 and 10 degrees C during the addition. Then added CbzCl (1195.36 mg, 7.008 mmol, 2.0 equiv). The resulting solution was stirred for 2h at 25 °C. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% FA) and MeCN (22.0% MeCN up to 98.0% in 7 min) to afford benzyl N-{[(1R,3R)-3-[(tert- butoxycarbonyl)amino]cyclopentyl]methyl}-N-methylcarbamate (210 mg, 16.54%) as a light yellow oil.

[0409] LCMS: m / z 362.5 [M+H]+24 5

[0410] Into a 8 mL vial werw added benzyl N-{[(1R,3R)-3-[(tert- butoxycarbonyl)amino]cyclopentyl]methyl}-N-methylcarbamate (210 mg, 0.579 mmol, 1 equiv), DCM (2 mL), HCl(gas)in 1,4-dioxane (2 mL, 23.608 mmol, 40.75 equiv). The resulting solution was stirred for 2h at 25 °C. The resulting mixture was concentrated under vacuum.This resulted in benzyl N-{[(1R,3R)-3-aminocyclopentyl]methyl}-N- methylcarbamate (170 mg, crude)as a light yeliow oil.

[0411] LCMS: m / z 262.4 [M+H]+Br N Br57

[0412] Into a 8 mL vial were added benzyl N-{[(1R,3R)-3-aminocyclopentyl]methyl}-N- methylcarbamate (172.66 mg, 0.658 mmol, 1.2 equiv), 6-bromo-2-chloro-8- methoxyquinazoline (150 mg, 0.548 mmol, 1.00 equiv), DIEA (425.29 mg, 3.288 mmol, 6.0 equiv) and n-BuOH (1.6 mL) for 2 h at 130oC. The crude product was purified by Prep- HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. This resulted in benzyl N-{[(1R,3R)-3-[(6-bromo-8-methoxyquinazolin-2-yl)amino]cyclopentyl]methyl}-N- methylcarbamate (150 mg, 54.77%) as a light yellow solid.

[0413] LCMS: m / z 499.4 [M+H]+7 9

[0414] Into a 8 mL vial and maintained with an inert atmosphere of nitrogen, were added benzyl N-{[(1R,3R)-3-[(6-bromo-8-methoxyquinazolin-2- yl)amino]cyclopentyl]methyl}-N-methylcarbamate (140 mg, 0.280 mmol, 1 equiv), bis(pinacolato)diboron (106.78 mg, 0.420 mmol, 1.5 equiv), KOAc (55.02 mg, 0.560 mmol, 2.0 equiv), dioxane (1.4 mL), Pd(dppf)Cl2 (10.26 mg, 0.014 mmol, 0.05 equiv). The resulting solution was stirred for 16 h at 90oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min) to afford benzyl N-{[(1R,3R)-3-{[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}cyclopentyl]methyl}-N-methylcarbamate (140 mg, 91.39%) as a light yellow solid.

[0415] LCMS: m / z 546.5 [M+H]+F OO) OH

[0416] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed benzyl N-{[(3S)-3-{[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl]amino}cyclopentyl]methyl}-N-methylcarbamate (130 mg, 0.238 mmol, 1 equiv), (1R)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (156.53 mg, 0.357 mmol, 1.5 equiv), K2CO3 (98.63 mg, 0.714 mmol, 3.0 equiv), dioxane (1.3 mL), Pd(dppf)Cl2(8.70 mg, 0.012 mmol, 0.05 equiv). The resulting solution was stirred for 16 h at 100oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min) to afford benzyl N-{[(3S)-3-[(6-{3-[(1R)-6-chloro-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamido]-2,6-difluorophenyl}-8-methoxyquinazolin-2- yl)amino]cyclopentyl]methyl}-N-methylcarbamate (120 mg, 64.82%) as a light yellow solid.

[0417] LCMS: RT = 0.789 min, m / z 778.3 [M+H]+OH10

[0418] Into a 8 ml vial was placed benzyl N-{[(3S)-3-[(6-{3-[(1R)-6-chloro-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl}-8-methoxyquinazolin-2- yl)amino]cyclopentyl]methyl}-N-methylcarbamate (70 mg, 0.090 mmol, 1 equiv),trifluoroacetaldehyde (1 mL). The resulting solution was stirred for 2 h at rt. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[(1R)-3- [(methylamino)methyl]cyclopentyl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide (33.6 mg, 56.08%) as a off white solid.

[0419] LCMS: RT = 2.498 min, m / z 644.2 [M+H]+

[0420] 1H NMR:1H NMR (400 MHz,CD3OD) δ 8.21 (s, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.70 (t, J = 1.5 Hz, 1H), 6.64 – 6.35 (m, 2H), 6.27 (s, 1H), 6.12 (t, J = 9.1 Hz, 1H), 4.33 (t, J = 6.8 Hz, 1H), 3.78 (q, J = 6.7 Hz, 1H), 3.18 (s, 3H), 2.20 (dt, J = 16.9, 8.0 Hz, 1H), 2.06 (d, J = 7.4 Hz, 2H), 1.81 (s, 3H), 1.64 (p, J = 7.6 Hz, 2H), 1.50 – 1.41 (m, 1H), 1.34 – 1.24 (m, 1H), 1.06 (dtd, J = 28.5, 14.2, 13.4, 7.8 Hz, 3H), 0.88 (dq, J = 14.6, 7.9 Hz, 1H), 0.65 – 0.48 (m, 1H), -0.79 (s, 6H). Example S-25: (1R)-6-chloro-N-[3-(2-{[2-(dimethylamino)propyl]amino}-8- methoxyquinazolin-6-yl)-2,4-difluorophenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 14) Br ClStep1 1 3

[0421] Into a 8-mL vial was placed 6-bromo-2-chloro-8-methoxyquinazoline (150 mg, 0.548 mmol, 1 equiv), tert-butyl N-(3-aminopropyl)-N-methylcarbamate (154.88 mg, 0.822 mmol, 1.5 equiv), DIEA (425.29 mg, 3.288 mmol, 6.0 equiv), n-BuOH (1.5 mL). The resulting solution was stirred for 4 h at 130 °C. The crude product was purified by Prep- HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. This resulted in tert-butyl N-{3-[(6-bromo-8-methoxyquinazolin-2-yl)amino]propyl}-N-methylcarbamate (200 mg, 85.74%) as a light yellow solid.

[0422] LCMS: RT = 1.367 min, m / z 425.1 [M+H]+O OB35

[0423] Into a 8 ml vial and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-{3-[(6-bromo-8-methoxyquinazolin-2-yl)amino]propyl}-N- methylcarbamate (200 mg, 0.470 mmol, 1 equiv), bis(pinacolato)diboron (179.11 mg, 0.705 mmol, 1.5 equiv), KOAc (92.30 mg, 0.940 mmol, 2.0 equiv), dioxane (2 mL), Pd(dppf)Cl2 (17.20 mg, 0.024 mmol, 0.05 equiv). The reaction mixture was stirred at 90 °C for 2 h. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. This resulted in tert-butyl N-(3-{[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-yl]amino}propyl)-N-methylcarbamate (180 mg, 81.03%) as a light yellow solid.

[0424] LCMS: m / z 472.4 [M+H]+) OH BocO, OCl Step3 56

[0425] Into a 8 ml vial and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-(3-{[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}propyl)-N-methylcarbamate (160 mg, 0.339 mmol, 1 equiv), (1R)- N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (148.58 mg, 0.339 mmol, 1 equiv), K2CO3 (140.43 mg, 1.017 mmol, 3.0 equiv), DMSO (1.6 mL), H2O (0.16 mL), RuPhos Palladacycle Gen.3 (14.60 mg, 0.017 mmol, 0.05 equiv). The reaction mixture was stirred at 90 °C for 2 h. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. This resulted in tert-butyl N-{3-[(6- {3-[(1R)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl}-8- methoxyquinazolin-2-yl)amino]propyl}-N-methylcarbamate (90 mg, 37.73%) as a light yellow solid.

[0426] LCMS: RT = 1.254 min, m / z 704.3 [M+H]+F F ) OH Bo67

[0427] Into a 8-mL vial, was placed tert-butyl N-{3-[(6-{3-[(1R)-6-chloro-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl}-8-methoxyquinazolin-2- yl)amino]propyl}-N-methylcarbamate (90 mg, 0.128 mmol, 1 equiv), HCl(gas)in 1,4-dioxane (1 mL, 32.913 mmol, 257.52 equiv), DCM (1 mL, 15.731 mmol, 123.08 equiv). The resulting solution was stirred for 1 h at rt. The resulting mixture was concentrated under vacuum. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[3- (methylamino)propyl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (30 mg, 38.86%) as a light yellow solid.

[0428] LCMS: RT = 0.707 min, m / z 604.1 [M+H]+) OH HN7

[0429] Into a 8-mL vial, was placed (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[2- (methylamino)ethyl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (60 mg, 0.102 mmol, 1 equiv), MeOH (1 mL), NaBH3CN (12.78 mg, 0.204 mmol, 2.0 equiv), HCHO (9.16 mg, 0.306 mmol, 3.0 equiv). The resulting solution was stirred for 2 h at rt. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in (1R)-6-chloro- N-[3-(2-{[2-(dimethylamino)propyl]amino}-8-methoxyquinazolin-6-yl)-2,4-difluorophenyl]- 1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (9 mg, 14.46%) as a off-white solid.

[0430] LCMS: RT = 1.078 min, m / z 618.2 [M+H]+

[0431] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 7.45 – 7.27 (m, 2H), 7.17 (s, 1H), 6.96 (t, J = 9.4 Hz, 1H), 5.14 (t, J = 6.7 Hz, 1H), 4.05 (s, 3H), 3.64 (t, J = 6.5 Hz, 2H), 3.34 (s, 1H), 3.00 (dt, J = 17.0, 8.0 Hz, 1H), 2.92 (s, 2H), 2.66 (s, 6H), 2.45 (d, J = 8.8 Hz, 1H), 2.04 (s, 2H), 1.88 (dq, J = 14.5, 7.9 Hz, 1H). Example S-25: (1R)-6-chloro-N-[3-(2-{[2-(dimethylamino)ethyl]amino}-8- methoxyquinazolin-6-yl)-2,4-difluorophenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 15) r Cl1 3

[0432] Into a 8-mL vial was placed 6-bromo-2-chloro-8-methoxyquinazoline (150 mg, 0.548 mmol, 1 equiv), tert-butyl N-(2-aminoethyl)-N-methylcarbamate (143.34 mg, 0.822 mmol, 1.5 equiv), DIEA (425.29 mg, 3.288 mmol, 6.0 equiv), n-BuOH (1.5 mL). The resulting solution was stirred for 4 h at 130 °C. The crude product was purified by Prep- HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBDColumn, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. This resulted in tert-butyl N-{2-[(6-bromo-8-methoxyquinazolin-2-yl)amino]ethyl}-N-methylcarbamate (190 mg, 84.23%) as a light yellow solid.

[0433] LCMS: m / z 411.3 [M+H]+O O

[0434] Into a 8 ml vial and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-{2-[(6-bromo-8-methoxyquinazolin-2-yl)amino]ethyl}-N- methylcarbamate (190 mg, 0.462 mmol, 1 equiv), bis(pinacolato)diboron (175.96 mg, 0.693 mmol, 1.5 equiv), KOAc (90.67 mg, 0.924 mmol, 2.0 equiv), dioxane (1.9 mL, 22.428 mmol, 48.55 equiv), Pd(dppf)Cl2 (16.90 mg, 0.023 mmol, 0.05 equiv). The reaction mixture was stirred at 90 °C for 2 h. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. This resulted in tert-butyl N-(2-{[8-methoxy-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}ethyl)-N- methylcarbamate (180 mg, 85.01%) as a light yellow solid.

[0435] LCMS: m / z 458.4 [M+H]+) OH5 6

[0436] Into a 8 ml vial and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-(2-{[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl]amino}ethyl)-N-methylcarbamate (160 mg, 0.349 mmol, 1.00 equiv), (1R)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (153.12 mg, 0.349 mmol, 1.00 equiv), K2CO3(144.73 mg, 1.047 mmol, 3.0 equiv), DMSO (1.6 mL), H2O (0.16 mL), RuPhos Palladacycle Gen.3 (14.60 mg, 0.017 mmol, 0.05 equiv). The reaction mixture was stirred at 90 °C for 2 h. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. This resulted in tert-butyl N-{2-[(6-{3-[(1R)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido]- 2,6-difluorophenyl}-8-methoxyquinazolin-2-yl)amino]ethyl}-N-methylcarbamate (150 mg, 62.26%) as a light yellow solid.

[0437] LCMS: RT = 0.884 min, m / z 690.2 [M+H]+) OH67

[0438] Into a 8-mL vial, was placedtert-butyl N-{2-[(6-{3-[(1R)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl}-8-methoxyquinazolin-2- yl)amino]ethyl}-N-methylcarbamate (145 mg, 0.210 mmol, 1 equiv), HCl(gas)in 1,4-dioxane (1.4 mL, 46.078 mmol, 219.32 equiv), DCM (1.4 mL, 22.023 mmol, 104.82 equiv). The resulting solution was stirred for 1 h at rt. The resulting mixture was concentrated under vacuum. This resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[2- (methylamino)ethyl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (100 mg, 80.67%) as a yellow solid.

[0439] LCMS: m / z 590.0 [M+H]+F F OO(R)O O(R) OH

[0440] Into a 8 ml vial, was placed(1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[2- (methylamino)ethyl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (60 mg, 0.102 mmol, 1 equiv), MeOH (1 mL), NaBH3CN (12.78 mg, 0.204 mmol, 2.0 equiv), HCHO (9.16 mg, 0.306 mmol, 3.0 equiv). The resulting solution was stirred for 2 h at rt. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in (1R)-6-chloro- N-[3-(2-{[2-(dimethylamino)ethyl]amino}-8-methoxyquinazolin-6-yl)-2,4-difluorophenyl]-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (9 mg, 14.46%) as a off-white solid.

[0441] LCMS: RT = 1.053 min, m / z 604.2 [M+H]+

[0442] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.12 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.42 – 7.32 (m, 2H), 7.16 (s, 1H), 6.98 (t, J = 9.2 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.05 (s, 3H), 3.75 (t, J = 5.5 Hz, 2H), 3.00 (dt, J = 16.7, 7.9 Hz, 1H), 2.75 (s, 6H), 2.47 (s, 1H), 1.89 (dt, J = 13.1, 7.3 Hz, 1H), 1.31 (s, 1H). Example S-26: (1R)-6-chloro-N-(2,4-difluoro-3-{8-methoxy-2-[(1-methylpiperidin-4- yl)amino]quinazolin-6-yl}phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 23) Br Cl1 3

[0443] Into a 40-mL vial were added 6-bromo-2-chloro-8-methoxyquinazoline (400 mg, 1.462 mmol, 1 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (439.36 mg, 2.193 mmol, 1.5 equiv), DIEA (1134.12 mg, 8.772 mmol, 6.0 equiv) and n-BuOH (4 mL). The resulting solution was stirred for 2 h at 130oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). To afford tert-butyl 4-[(6-bromo-8-methoxyquinazolin-2- yl)amino]piperidine-1-carboxylate (590 mg, 92.25%) as a light yellow solid.

[0444] LCMS: RT = 1.928 min, m / z 437.1 [M+H]+Bo

[0445] Into a 40-mL vial, and maintained with an inert atmosphere of nitrogen, were added tert-butyl 4-[(6-bromo-8-methoxyquinazolin-2-yl)amino]piperidine-1-carboxylate (590 mg, 1.349 mmol, 1 equiv), bis(pinacolato)diboron (513.87 mg, 2.023 mmol, 1.5 equiv), KOAc (264.80 mg, 2.698 mmol, 2.0 equiv), dioxane (6 mL), Pd(dppf)Cl2 (49.36 mg, 0.067 mmol, 0.05 equiv). The reaction mixture was stirred for 16 h at 90oC. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). To afford tert-butyl 4-{[8-methoxy-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1-carboxylate (600 mg, 91.81%) as a light yellow solid.

[0446] LCMS: RT = 1.738 min, m / z 485.2 [M+H]+)BocOHO Step3 5 6

[0447] Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 4-{[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl]amino}piperidine-1-carboxylate (265.02 mg, 0.547 mmol, 1.5 equiv), (1R)-N-(3-bromo- 2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (160 mg, 0.365 mmol, 1.00 equiv), K2CO3(151.23 mg, 1.095 mmol, 3.0 equiv), dioxane (1.6 mL), H2O (0.16 mL), Pd(dppf)Cl2(13.34 mg, 0.018 mmol, 0.05 equiv) for 16 h at 100oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min) to afford tert-butyl 4-[(6-{3- [(1R)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl}-8- methoxyquinazolin-2-yl)amino]piperidine-1-carboxylate (150 mg, 57.42%) as a brown yellow solid.

[0448] LCMS: RT = 1.693 min, m / z 716.1 [M+H]+F F R) BoOH67

[0449] Into a 8ml vial, were added tert-butyl 4-[(6-{3-[(1R)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl}-8-methoxyquinazolin-2- yl)amino]piperidine-1-carboxylate (150 mg, 0.209 mmol, 1 equiv), DCM (1.5 mL) and TFA (0.3 mL, 4.039 mmol, 19.28 equiv). The reaction mixture was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. To afford (1R)-6-chloro-N-{2,4- difluoro-3-[8-methoxy-2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (130 mg, curde) as a brown yellow oil.

[0450] LCMS: RT = 1.039 min, m / z 616.0 [M+H]+F F OO(R)O O (R)H OH

[0451] Into a 8 ml vial were added (1R)-6-chloro-N-{2,4-difluoro-3-[8-methoxy-2- (piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (110 mg, 0.179 mmol, 1 equiv), MeOH (1.1 mL), HCHO (16.08 mg, 0.537 mmol, 3.0 equiv), NaBH3CN (22.44 mg, 0.358 mmol, 2.0 equiv). The resulting solution was stirred for 2 h at rt. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). Lyophilization. To afford (1R)-6-chloro-N-(2,4-difluoro-3-{8-methoxy-2-[(1- methylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (30.2 mg, 26.12%) as a off white solid.

[0452] LCMS: RT = 1.014 min, m / z 630.2 [M+H]+

[0453] 1H NMR:1H NMR (400 MHz,CD3OD) δ 9.04 (s, 1H), 7.60 (d, J = 14.5 Hz, 2H), 7.49 – 7.38 (m, 1H), 7.30 (s, 1H), 7.11 – 7.00 (m, 2H), 5.15 (t, J = 6.8 Hz, 1H), 4.12 (s, 1H), 3.99 (s, 4H), 3.63 (q, J = 7.0 Hz, 0H), 3.26 (dd, J = 8.6, 3.9 Hz, 1H), 2.97 (dt, J = 16.8, 8.7 Hz, 4H), 2.47 (dt, J = 12.3, 6.0 Hz, 1H), 2.39 (s, 5H), 2.34 (s, 1H), 2.13 (d, J = 13.0 Hz, 3H), 1.88 (dq, J = 14.8, 7.8 Hz, 1H), 1.72 (t, J = 11.6 Hz, 2H), 1.33 (d, J = 11.4 Hz, 1H). Example S-27:6-chloro-N-[2,4-difluoro-3-(2-{[1-(2-methoxyethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-2,3-dihydro-1-benzofuran-4-sulfonamide (Compound 24)- ,ClBrCl Br step1 1 3

[0454] Into a 100ml three-necked flask was placed chloro(methoxymethyl)triphenyl- lambda5-phosphane (2.99 g, 8.714 mmol, 1.3 equiv), THF(100mL), t-BuLi (0.56 g, 8.714 mmol, 1.3 equiv), The resulting solution was stirred for 0.5 h at 0 °C, This was adding 2,6- dibromo-4-chlorobenzaldehyde (2 g, 6.703 mmol, 1 equiv), The resulting solution was stirred for 16 hour at RT, The reaction was then quenched by the addition of 50 mL of saturated aqueous NH4Cl, The resulting solution was extracted with 3x100 mL of EA. The resulting mixture was washed with 1 x100 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated, The result in 1,3-dibromo-5-chloro-2-[(E)-2- methoxyethenyl]benzene (1.56 g, 71.30%) as yellow solid.

[0455] LCMS: RT = 2.165min, m / z 327.2 [M-H]+Br Br O Cl

[0456] Into a 50 mL vial were added 1,3-dibromo-5-chloro-2-[(E)-2- methoxyethenyl]benzene (1.5 g, 4.595 mmol, 1 equiv), HCl(6mL), Ether(15mL), The resulting solution was stirred for 3 hour at RT, The resulting solution was diluted with 20 mL of water. The pH value of the solution was adjusted to 8-9 with NaHCO3. The aqueous phase was extracted with 3x50 mL of ethyl acetate. The organic layers were washed with 2 x40 ml of brine, dried over anhydrous sodium sulfate and concentrated. The result in 2-(2,6-dibromo- 4-chlorophenyl)acetaldehyde (1.36 g, 94.74%) as grey solid.

[0457] LCMS: m / z 313 [M+H]+O.,ClBrClBrstep2 34

[0458] Into a 50 mL vial were added 1,3-dibromo-5-chloro-2-[(E)-2- methoxyethenyl]benzene (1.5 g, 4.595 mmol, 1 equiv), HCl(6mL), Ether(15mL), The resulting solution was stirred for 3 hour at RT, The resulting solution was diluted with 20 mL of water The pH value of the solution was adjusted to 8-9 with NaHCO3 The aqueous phasewas extracted with 3x50 mL of ethyl acetate. The organic layers were washed with 2 x40 ml of brine, dried over anhydrous sodium sulfate and concentrated. The result in 2-(2,6-dibromo- 4-chlorophenyl)acetaldehyde (1.36 g, 94.74%) as grey solid.

[0459] LCMS: m / z 313 [M+H]+Br Br H Cl

[0460] Into a 50-mL round-bottom was placed 2-(2,6-dibromo-4- chlorophenyl)acetaldehyde (1.36 g, 4.354 mmol, 1 equiv), NaBH4 (0.33 g, 8.708 mmol, 2 equiv) and MeOH（20 mL）, The resulting solution was stirred for 2 hour at RT, The reaction was then quenched by the addition of 30 mL of saturated aqueous NaHCO3. The resulting solution was extracted with 3x50 mL of EA. The resulting mixture was washed with 1 x30 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 2-(2,6-dibromo-4-chlorophenyl)ethanol (1.2 g, 87.67%) as white solid.

[0461] LCMS: m / z 315 [M+H]+Cl5

[0462] Into a 40 mL vial with an inert atmosphere of nitrogen was placed 2-(2,6- dibromo-4-chlorophenyl)ethanol (1.2 g, 3.817 mmol, 1 equiv), t-BuOLi (0.92 g, 11.451 mmol, 3 equiv), CuI (0.07 g, 0.382 mmol, 0.1 equiv), dioxane(15 mL), The resulting solution was stirred for 4 hour at 120oC, The reaction was then quenched by the addition of 20 mL of saturated aqueous NH4Cl. The resulting solution was extracted with 3x20 mL of EA. The resulting mixture was washed with 1 x20 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was further purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, Water (0.1% FA) and CH3CN (30% CH3CN up to 98% in 4 min); Detector, UV 254 &220nm. The mixture was concentrated. This resulted in 4-bromo-6-chloro-2,3-dihydro-1- benzofuran (520 mg, 58.35%) as white solid.

[0463] LCMS: m / z 233 [M+H]+Br O6 7

[0464] Into a 40 mL vial with an inert atmosphere of nitrogen was placed 4-bromo-6- chloro-2,3-dihydro-1-benzofuran (470 mg, 2.013 mmol, 1 equiv), benzyl mercaptan (500.01 mg, 4.026 mmol, 2 equiv), Pd2(dba)3(92.17 mg, 0.101 mmol, 0.05 equiv), Xantphos (116.47 mg, 0.201 mmol, 0.1 equiv), DIEA (780.50 mg, 6.039 mmol, 3 equiv) and dioxane (5mL), The resulting solution was stirred for 2 hour at 120oC, The crude mixture was directly purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel (120 g); mobile phase, Water (0.1% FA) and ACN (30% ACN up to 98% in 4 min, 98% ACN to 98% in 3 min); Total flow rate, 70 mL / min; Detector, UV 220 nm. The collected fractions were concentrated under reduced pressure. This resulted in 4-(benzylsulfanyl)-6-chloro-2,3- dihydro-1-benzofuran (460 mg, 82.56%) as colorless oil.

[0465] LCMS: RT = 2.037min, m / z 275 [M-H]+78

[0466] Into a 40 mL vial with an inert atmosphere of nitrogen was placed 4- (benzylsulfanyl)-6-chloro-2,3-dihydro-1-benzofuran (460 mg, 1.662 mmol, 1 equiv), NCS (244.12 mg, 1.828 mmol, 1.1 equiv), AcOH(5mL)，H2O(1mL), The resulting solution was stirred for 2 hour at 0oC-RT, The reaction was then quenched by the addition of 20 mL H2O. The resulting solution was extracted with 3x30 mL of EA. The resulting mixture was washed with 1 x30 ml of brine. The mixture was dried over anhydrous sodium sulfate andconcentrated. This resulted in 6-chloro-2,3-dihydro-1-benzofuran-4-sulfonyl chloride (430 mg, 102.23%) as yellow oil.

[0467] LCMS:m / z 253 [M+H]+FOO Cl

[0468] Into a 40 mL vial was placed 6-chloro-2,3-dihydro-1-benzofuran-4-sulfonyl chloride (230 mg, 0.909 mmol, 1 equiv), 3-bromo-2,4-difluoroaniline (189.03 mg, 0.909 mmol, 1 equiv), py (436.79 mg, 5.454 mmol, 6 equiv)，DCM(3mL), The resulting solution was stirred for 2 hour at RT, The crude mixture was directly purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel (120 g); mobile phase, Water (0.1% FA) and ACN (30% ACN up to 98% in 4 min, 98% ACN to 98% in 3 min); Total flow rate, 70 mL / min; Detector, UV 220 nm. The collected fractions were concentrated under reduced pressure. This resulted in N-(3-bromo-2,4-difluorophenyl)-6-chloro-2,3-dihydro-1- benzofuran-4-sulfonamide (170 mg, 44.05%) as yellow solid.

[0469] LCMS: RT = 1.754min, m / z 423.8 [M-H]+F O BrCl Step8

[0470] Into a 40 mL vial with an inert atmosphere of nitrogen was placed N-(3-bromo- 2,4-difluorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-4-sulfonamide (70 mg, 0.165 mmol, 1 equiv), N-[1-(2-methoxyethyl)piperidin-4-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-amine (67.97 mg, 0.165 mmol, 1 equiv), Pd(dppf)Cl2 (12.06 mg, 0.017 mmol, 0.1 equiv), K2CO3(68.35 mg, 0.495 mmol, 3 equiv), dioxane(1mL), H2O(0.1mL), Theresulting solution was stirred for 2 hour at 100oC, The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and CH3CN (16% CH3CN up to 34% in 10 min); Detector, UV 220&254 nm. Lyophilization, This resulted in 6-chloro-N- [2,4-difluoro-3-(2-{[1-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-2,3- dihydro-1-benzofuran-4-sulfonamide (15.2 mg, 14.63%) as off-white solid.

[0471] LCMS: RT = 1.091min, m / z 630.1 [M+H]+

[0472] 1H NMR: 1H NMR (300 MHz, Chloroform-d) δ 8.98 (s, 1H), 7.64 (s, 3H), 7.55 (td, J = 8.9, 5.5 Hz, 1H), 7.28 (d, J = 5.1 Hz, 1H), 7.04 (td, J = 8.9, 1.7 Hz, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.25 (s, 2H), 5.68 (d, J = 7.9 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H), 4.13 (d, J = 9.2 Hz, 1H), 3.63 (t, J = 5.4 Hz, 2H), 3.39 (s, 3H), 3.38 (d, J = 17.5 Hz, 1H), 3.12 (d, J = 11.9 Hz, 2H), 2.79 (t, J = 5.4 Hz, 2H), 2.51 (t, J = 11.1 Hz, 2H), 2.21 (d, J = 12.7 Hz, 2H), 1.81 (q, J = 10.5 Hz, 2H), 1.28 (s, 0H). Example S-28: (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[1-(2- methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (Compound 26) Br Cl1 3

[0473] Into a 100-mL round-bottom flask were added 6-bromo-2-chloro-8- methoxyquinazoline (1 g, 3.656 mmol, 1 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (1.10 g, 5.484 mmol, 1.5 equiv), DIEA (2.84 g, 21.936 mmol, 6.0 equiv) and n-BuOH (10 mL) for 2 h at 130 °C. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). To afford tert-butyl 4-[(6-bromo-8-methoxyquinazolin-2-yl)amino]piperidine-1-carboxylate (1.4 g, 87.56%) as a light yellow solid.

[0474] LCMS: m / z 437.3 [M+H]+O O B

[0475] Into a 100-mL round-bottom flask, and maintained with an inert atmosphere of nitrogen, were added tert-butyl 4-[(6-bromo-8-methoxyquinazolin-2-yl)amino]piperidine-1- carboxylate (1.4 g, 3.201 mmol, 1 equiv), bis(pinacolato)diboron (1.22 g, 4.801 mmol, 1.5 equiv), KOAc (0.63 g, 6.402 mmol, 2.0 equiv), dioxane (14 mL), Pd(dppf)Cl2(0.12 g, 0.160 mmol, 0.05 equiv). The reaction mixture was stirred for 16 h at 90 ℃. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). To afford tert-butyl 4-{[8-methoxy-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1-carboxylate (1.3 g, 83.84%) as a light yellow solid.

[0476] LCMS: m / z 484.4 [M+H]+)BocOH6

[0477] Into a 8 mL vial were added tert-butyl 4-{[8-methoxy-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1-carboxylate (248.46 mg, 0.513 mmol, 1.5 equiv), (1R)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide (150 mg, 0.342 mmol, 1.00 equiv), K2CO3(141.77 mg, 1.026 mmol, 3.0 equiv), dioxane (1.5 mL), H2O (0.15 mL), Pd(dppf)Cl2 (12.51 mg, 0.017 mmol, 0.05 equiv) for 16 h at 100 ℃. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to98.0% in 7 min) to afford tert-butyl 4-[(6-{3-[(1R)-6-chloro-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamido]-2,6-difluorophenyl}-8-hydroxyquinazolin-2-yl)amino]piperidine-1- carboxylate (130 mg, 54.14%) as a light yellow solid.

[0478] LCMS: RT = 1.918 min, m / z 718.1 [M+H]+F TF F OOA OOBoO) H67

[0479] Into a 8ml vial, were added tert-butyl 4-[(6-{3-[(1R)-6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamido]-2,6-difluorophenyl}-8-methoxyquinazolin-2- yl)amino]piperidine-1-carboxylate (160 mg, 0.223 mmol, 1 equiv), DCM (1.6 mL) and TFA (0.32 mL, 4.308 mmol, 19.28 equiv). The reaction mixture was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. To afford (1R)-6-chloro-N-{2,4- difluoro-3-[8-methoxy-2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (170 mg, crude) as a light yellow oil.

[0480] LCMS: RT =1.188 min, m / z 616.0 [M+H]+) OH HN7

[0481] Into a 8 mL vial were dded (1R)-6-chloro-N-{2,4-difluoro-3-[8-methoxy-2- (piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (160 mg, 0.260 mmol, 1 equiv), DMF (1.6 mL), K2CO3 (107.68 mg, 0.780 mmol, 3.0 equiv), ethane, 1-chloro-2-methoxy- (49.11 mg, 0.520 mmol, 2.0 equiv). The resulting solution was stirred for 16 h at 70 ℃. The crude product was purified by Prep- HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). Lyophilization. To afford (1R)-6-chloro-N-[2,4-difluoro-3-(8-methoxy-2-{[1-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamide (58.7 mg, 32.92%) as a off white solid.

[0482] LCMS: RT = 2.456 min, m / z 674.2 [M+H]+

[0483] 1H NMR:1H NMR (300 MHz,CD3OD) δ 9.03 (s, 1H), 7.64 – 7.56 (m, 2H), 7.45 (td, J = 8.8, 5.7 Hz, 1H), 7.29 (s, 1H), 7.08 (td, J = 9.1, 1.8 Hz, 1H), 7.01 (s, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.12 (s, 1H), 3.98 (s, 3H), 3.60 (t, J = 5.5 Hz, 2H), 3.38 (s, 3H), 3.31 – 3.18 (m, 1H), 3.08 (d, J = 11.5 Hz, 2H), 3.03 – 2.87 (m, 1H), 2.73 (t, J = 5.6 Hz, 2H), 2.43 (t, J = 11.3 Hz, 3H), 2.12 (d, J = 12.7 Hz, 2H), 1.97 – 1.79 (m, 1H), 1.75 (d, J = 11.2 Hz, 1H), 1.68 (d, J = 10.5 Hz, 1H). Example S-29: 6-chloro-N-{2,4-difluoro-3-[8-methoxy-2-(piperidin-3- ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 30) Br Cl

[0484] Into a 8 mL vial were added 2,6-dibromo-8-methoxyquinazoline (200 mg, 0.629 mmol, 1 equiv), tert-butyl 3-aminopiperidine-1-carboxylate (188.96 mg, 0.944 mmol, 1.5 equiv), DIEA (487.77 mg, 3.774 mmol, 6.0 equiv) and n-BuOH (2 mL) for 2 h at 130oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. This resulted in tert-butyl 3-[(6-bromo-8-methoxyquinazolin-2-yl)amino]piperidine- 1-carboxylate (120 mg, 43.62%) as a light yellow solid.

[0485] LCMS: RT = 0.809 min, m / z 437.1 [M+H]+O O O Bo

[0486] Into a 8 mL vial and maintained with an inert atmosphere of nitrogen, ewre placed tert-butyl 3-[(6-bromo-8-methoxyquinazolin-2-yl)amino]piperidine-1-carboxylate (120 mg, 0.274 mmol, 1 equiv), bis(pinacolato)diboron (104.52 mg, 0.411 mmol, 1.5 equiv), KOAc (53.86 mg, 0.548 mmol, 2.0 equiv), dioxane (1.2 mL), Pd(dppf)Cl2 (10.04 mg, 0.014 mmol, 0.05 equiv) for 16 h at 90oC. The resulting mixture was concentrated under reduced pressure. The product was used in the next step directly without further purification.

[0487] LCMS: RT = 1.863 min, m / z 485.3 [M+H]+F OH Boc

[0488] Into a 8 mL vial and maintained with an inert atmosphere of nitrogen, were added tert-butyl 3-{[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl]amino}piperidine-1-carboxylate (120 mg, 0.248 mmol, 1 equiv), N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (163.01 mg, 0.372 mmol, 1.5 equiv), K2CO3 (102.71 mg, 0.744 mmol, 3.0 equiv), dioxane (1.2 mL), H2O (0.12 mL), Pd(dppf)Cl2(9.06 mg, 0.012 mmol, 0.05 equiv) for 16 h at 100oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min) to afford tert-butyl 3-({6-[3-(6- chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)-2,6-difluorophenyl]-8- methoxyquinazolin-2-yl}amino)piperidine-1-carboxylate (100 mg, 56.36%) as a light yellow solid.

[0489] LCMS: RT = 1.669 min, m / z 716.3 [M+H]+F F OO O OOH Bo

[0490] Into a 8 mL vial were added tert-butyl 3-({6-[3-(6-chloro-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamido)-2,6-difluorophenyl]-8-methoxyquinazolin-2-yl}amino)piperidine- 1-carboxylate (100 mg, 0.140 mmol, 1 equiv), DCM (1 mL, 15.731 mmol, 112.66 equiv) and TFA (0.2 mL, 2.693 mmol, 19.28 equiv) for 2 h at 25oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). Lyophilization. To afford 6-chloro-N-{2,4- difluoro-3-[8-methoxy-2-(piperidin-3-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (22.4 mg, 25.94%) as a off white solid.

[0491] LCMS : RT = 1.080 min, m / z 616.2 [M+H]+

[0492] 1H NMR :1H NMR (400 MHz,CD3OD) δ 9.10 (s, 1H), 8.56 (s, 1H), 7.60 (s, 2H), 7.47 (td, J = 8.9, 5.7 Hz, 1H), 7.34 (s, 1H), 7.17 – 7.08 (m, 1H), 7.06 (s, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.36 (dt, J = 8.8, 4.6 Hz, 1H), 4.00 (s, 3H), 3.64 (dd, J = 12.3, 4.1 Hz, 1H), 3.24 (ddd, J = 17.3, 8.6, 3.8 Hz, 1H), 3.14 – 3.04 (m, 2H), 2.95 (dt, J = 17.0, 8.1 Hz, 1H), 2.52 – 2.40 (m, 1H), 2.17 (d, J = 14.9 Hz, 1H), 2.10 (s, 1H), 1.94 – 1.77 (m, 2H). Example S-30: 6-chloro-N-[2,4-difluoro-3-(2-{[1-(oxolan-2-ylmethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 31)B13

[0493] Into a 50-mL round-bottom flask and maintained with an inert atmosphere of nitrogen, were added tert-butyl 4-[(6-bromoquinazolin-2-yl)amino]piperidine-1-carboxylate (500 mg, 1.228 mmol, 1 equiv), bis(pinacolato)diboron (467.59 mg, 1.842 mmol, 1.5 equiv), KOAc (240.95 mg, 2.456 mmol, 2.0 equiv), dioxane (5 mL), Pd(dppf)Cl2 (44.91 mg, 0.061 mmol, 0.05 equiv) for 2 h at 90oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min) to afford tert-butyl 4-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl]amino}piperidine-1-carboxylate (360 mg, 64.54%) as a light yellow solid.

[0494] LCMS: m / z 454.4 [M+H]+FBocOH

[0495] Into a 8 mL vial and maintained with an inert atmosphere of nitrogen, were added tert-butyl 4-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl]amino}piperidine-1-carboxylate (150 mg, 0.330 mmol, 1 equiv), N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (217.22 mg, 0.495 mmol, 1.5 equiv), K2CO3 (136.87 mg, 0.990 mmol, 3.0 equiv), dioxane (2 mL), H2O (0.2 mL), Pd(dppf)Cl2(12.08 mg, 0.017 mmol, 0.05 equiv) for 16 h at 100oC. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min) to afford tert-butyl 4-({6-[3-(6- chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)-2,6-difluorophenyl]quinazolin-2- yl}amino)piperidine-1-carboxylate (140 mg, 61.81%) as a light yellow solid.

[0496] LCMS: m / z 686.2 [M+H]+F F OO O OBoc OH

[0497] Into a 8 mL vial were added tert-butyl 4-({6-[3-(6-chloro-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamido)-2,6-difluorophenyl]quinazolin-2-yl}amino)piperidine-1- carboxylate (140 mg, 0.204 mmol, 1 equiv), DCM (1.4 mL), TFA (0.3 mL, 4.039 mmol, 19.80 equiv) for 2 h at rt. The resulting mixture was concentrated under reduced pressure. The product was used in the next step directly without further purification. To afford 6- chloro-N-{2,4-difluoro-3-[2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (120 mg, 100.36%) as a off white solid.

[0498] LCMS: RT = 0.572 min, m / z 586.3 [M+H]+F FHNOH5

[0499] Into a 8 mL vial were added 6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4- ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (60 mg, 0.102 mmol, 1 equiv), 2-(bromomethyl)oxolane (33.79 mg, 0.204 mmol, 2.0 equiv), K2CO3 (42.45 mg, 0.306 mmol, 3.0 equiv) and DMF (1 mL) for 2 h at 60oC. The resulting mixture was filtered. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 98.0% in 7 min). Lyophilization. To afford 6-chloro-N-[2,4-difluoro-3-(2-{[1-(oxolan-2-ylmethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (22.8 mg, 31.61%) as a off white solid.

[0500] LCMS: RT = 1.522 min, m / z 670.2 [M+H]+

[0501] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 7.69 (s, 1H), 7.60 (dt, J = 5.4, 2.8 Hz, 4H), 7.45 (td, J = 8.9, 5.7 Hz, 1H), 7.13 – 7.04 (m, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.18 – 4.08 (m, 1H), 4.08 – 3.98 (m, 1H), 3.95 – 3.85 (m, 1H), 3.83 – 3.73 (m, 1H), 3.29 –3.21 (m, 1H), 3.19 (s, 1H), 3.11 (s, 1H), 2.95 (dt, J = 16.8, 8.0 Hz, 1H), 2.69 – 2.56 (m, 2H), 2.45 (q, J = 11.2 Hz, 3H), 2.11 (s, 3H), 2.15 – 2.03 (m, 1H), 1.98 – 1.84 (m, 1H), 1.75 (t, J = 12.0 Hz, 2H), 1.56 (dq, J = 12.1, 8.0 Hz, 1H). Example S-31: 6-chloro-N-(2,4-difluoro-3-{2-[(1-isopropylpiperidin-4- yl)amino]quinazolin-6-yl}phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 33) F OHBr

[0502] Into a 8 mL vial with an inert atmosphere of nitrogen were added N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (100 mg, 0.228 mmol, 1 equiv), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (68.73 mg, 0.251 mmol, 1.1 equiv), RuPhos Palladacycle Gen.3(19.07 mg, 0.023 mmol, 0.1 equiv), K2CO3(94.52 mg, 0.684 mmol, 3 equiv) and dioxane(1mL), H2O(0.1mL) (10:1), The resulting solution was stirred for 1.5 h at 100 °C. In the reaction system, 82%P in LCMS, the product was used in the next step directly without further purification.

[0503] LCMS:m / z 506 [M+H]+OH F3

[0504] Into a 8 mL vial were added 6-chloro-N-[2,4-difluoro-3-(2-fluoroquinazolin-6- yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (90 mg, 0.178 mmol, 1 equiv), 1-isopropylpiperidin-4-amine (25.31 mg, 0.178 mmol, 1 equiv), DIEA (68.98 mg, 0.534mmol, 3 equiv) and DMSO（1.5mL）, The resulting solution was stirred for 2 h at 100 °C. The crude product (5 mL) was purified by Prep-HPLC with the following conditions(2#- analyse-HPLC-SHIMADZU(HPLC-01)): Column, XBridge prep OBD 19*150mm 5um C- 01; mobile phase, Water(0.1% NH3.H2O ) and ACN( ACN 30% up to 50% in 7 min); Detector, UV 254 &220 nm. Lyophilization. This resulted in 6-chloro-N-(2,4-difluoro-3-{2- [(1-isopropylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-1-hydroxy-2,3-dihydro-1H- indene-4-sulfonamide (12 mg, 9.5%) as a off white solid.

[0505] LCMS: RT = 1.205 min, m / z 628.3 [M+H]+

[0506] 1H NMR: 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.76 (s, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.57 – 7.47 (m, 3H), 7.23 – 7.15 (m, 1H), 7.03 (s, 1H), 5.50 (d, J = 5.8 Hz, 1H), 5.03 (q, J = 6.6 Hz, 1H), 4.00 (s, 1H), 3.11 (s, 3H), 2.81 (dt, J = 16.8, 8.2 Hz, 1H), 2.31 (s, 1H), 2.04 (s, 2H), 1.78 – 1.65 (m, 1H), 1.24 (s, 1H), 1.11 (s, 6H). Example S-32: 6-chloro-N-[2,4-difluoro-3-(2-{[1-(2,2,2-trifluoroethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 34) F OHBr1 3

[0507] Into a 8 mL vial with an inert atmosphere of nitrogen were added N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (100 mg, 0.228 mmol, 1 equiv), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (68.73 mg, 0.251 mmol, 1.1 equiv), RuPhos Palladacycle Gen.3(19.07 mg, 0.023 mmol, 0.1 equiv), K2CO3 (94.52 mg, 0.684 mmol, 3 equiv) and dioxane(1mL), H2O(0.1mL) (10:1), The resulting solution was stirred for 1.5 h at 100 °C. In the reaction system, 82% P in LCMS, the product was used in the next step directly without further purification.

[0508] LCMS: m / z 506 [M+H]+F F3C N F OOOH F

[0509] Into a 8 mL vial with an inert atmosphere of nitrogen were added 6-chloro-N-[2,4- difluoro-3-(2-fluoroquinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (100 mg, 0.198 mmol, 1 equiv) ,1-(2,2,2-trifluoroethyl)piperidin-4-amine (36.01 mg, 0.198 mmol, 1 equiv), DIEA (76.64 mg, 0.594 mmol,3 equiv) and DMSO(1.5 mL), The resulting solution was stirred for 2 h at 100 °C. The crude product(5 mL) was purified by Prep-HPLC with the following conditions(2#-analyse-HPLC-SHIMADZU(HPLC-01)): Column, XBridge prep OBD 19*150mm 5um C-01; mobile phase, Water(0.1% NH3.H2O ) and ACN( ACN 30% up to 50% in 7 min); Detector, UV 254 &220 nm. Lyophilization. This resulted in 6-chloro-N-[2,4-difluoro-3-(2-{[1-(2,2,2-trifluoroethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (14 mg, 10.50%) as a off white solid.

[0510] LCMS: RT = 2.972 min, m / z 668.2 [M+H]+

[0511] 1H NMR: 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.14 (s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.53 (d, J = 7.4 Hz, 4H), 7.26 (s, 1H), 7.21 (s, 1H), 5.60 (d, J = 5.5 Hz, 1H), 5.05 (d, J = 6.5 Hz, 1H), 3.89 (s, 1H), 3.22 – 3.12 (m, 1H), 3.06 (s, 1H), 2.95 (d, J = 11.2 Hz, 2H), 2.83 – 2.74 (m, 1H), 2.01 (s, 0H), 1.90 (s, 2H), 1.73 (s, 1H), 1.63 – 1.55 (m, 2H), 1.24 (s, 2H), 0.86 (s, 0H). Example S-33: 6-chloro-N-[2,4-difluoro-3-(2-{[1-(2-methoxyethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 39)Boc N Br Cl1 3

[0512] Into a 250 mL vial with an inert atmosphere of nitrogen were added 6-bromo-2- chloroquinazoline (10 g, 41.069 mmol, 1 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (9.05 g, 45.176 mmol, 1.1 equiv), DIEA (10.62 g, 82.138 mmol, 2 equiv) and n-BuOH（100 mL）for 4 h at 130 °C. The residue was diluted with water(100 ml). The resulting solution was extracted with 3x100 mL of ethyl acetate. The organic lays were washed with 1 x150 ml of brine, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). The collected fractions were combined and concentrated. This resulted in tert-butyl 4-[(6-bromoquinazolin-2- yl)amino]piperidine-1-carboxylate (14 g, 83.69%) as a white solid.

[0513] LCMS: RT = 1.675 min, m / z 407.1, 409.1 [M+H]+Bo3 5

[0514] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl -[(6-bromoquinazolin-2-yl)amino]piperidine-1-carboxylate (400 mg, 0.982 mmol, 1 equiv), bis(pinacolato)diboron（274.32 mg, 1.080mmol, 1.1 equiv）, Pd(dppf)Cl2(35.93 mg, 0.049 mmol, 0.05 equiv) , KOAc (289.14 mg, 2.946 mmol, 2equiv) , dioxane(4 mL) . The resulting solution was stirred for 2 h at 90 °C.94% P in LCMS. The product was used in the next step directly without further purification.

[0515] LCMS: RT = 0.746 min, m / z 455.4 [M+H]+F OOBoc OH

[0516] Into a 40 mL vial with an inert atmosphere of nitrogen were added tert-butyl 4- {[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1- carboxylate (400 mg, 0.880 mmol, 1 equiv), N-(3-bromo-2, 4-difluorophenyl)-6-chloro-1- hydroxy-2, 3-dihydro-1H-indene-4-sulfonamide (386.17 mg, 0.880 mmol, 1 equiv) , Pd(dppf)Cl2 (32.21 mg, 0.044 mmol, 0.05 equiv) , K2CO3 (364.99 mg, 2.640 mmol, 3 equiv) , and H2O (0.4 mL), dioxane (4 mL). The resulting solution was stirred for 4 h at 100oC. The crude mixture was directly purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel (120 g); mobile phase, Water (0.1% FA) and ACN (30% ACN up to 98% in 6 min, 98% ACN to 98% in 3 min); Total flow rate, 70 mL / min; Detector, UV 254 nm. The collected fractions were concentrated under reduced pressure. This resulted in tert- butyl 4-({6-[3-(6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)-2,6- difluorophenyl]quinazolin-2-yl}amino)piperidine-1-carboxylate (410 mg, 67.88%) as a brown solid.

[0517] LCMS: RT = 0.689 min, m / z 686.4 [M+H]+BoOH78

[0518] Into a 40 mL vial were added tert-butyl 4-({6-[3-(6-chloro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamido)-2,6-difluorophenyl]quinazolin-2-yl}amino)piperidine-1- carboxylate (410 mg, 0.598 mmol, 1 equiv) and TFA(1mL), DCM(5mL). The resulting solution was stirred for 2 h at rt. The reaction was concentrated under vacuum. This resulted in 6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamide (420 mg, 119.94%) as a yellow syrup.

[0519] LCMS: RT = 0.789 min, m / z 586.2 [M+H]+F OOO F HN OH

[0520] Into a 8-mL vial was placed 6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4- ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (400 mg, 0.683 mmol, 1 equiv), ethane, 1-chloro-2-methoxy- (193.58 mg, 2.049 mmol, 3 equiv), K2CO3 (282.99 mg, 2.049 mmol, 3 equiv). The resulting solution was stirred for 16 h at 70oC. The crude product was further purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase, Water (0.05% FA) and CH3CN (16% CH3CN up to 34% in 10 min); Detector, UV 220&254 nm. This resulted in 6-chloro-N-[2,4-difluoro-3-(2-{[1-(2-methoxyethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (115 mg, 26.16%) as a off-white solid.

[0521] LCMS: RT = 1.083 min, m / z 644.3 [M+H]+

[0522] 1H NMR: 1H NMR (300 MHz, Methanol-d4) δ 9.10 (s, 1H), 7.73 (s, 1H), 7.61 (dd, J = 2.7, 1.4 Hz, 4H), 7.47 (td, J = 8.9, 5.7 Hz, 1H), 7.18 – 7.06 (m, 1H), 5.16 (t, J = 6.8 Hz, 1H), 3.80 – 3.71 (m, 2H), 3.61 (d, J = 13.4 Hz, 3H), 3.45 (s, 3H), 3.36 (s, 1H), 3.30 – 3.16 (m, 2H), 2.94 (dt, J = 17.0, 8.0 Hz, 1H), 2.51 – 2.36 (m, 2H), 2.33 (s, 1H), 2.02 – 1.82 (m, 3H) Example S-34: (1S)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(2-methoxyethyl)piperidin-4- yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 41)O Fassumed, t=3.798 min

[0523] The 80 mg of Compound 39 was further purified by purified by Chiral-Prep- HPLC with the following conditions: Instrument Name: Chiral analyse-30-6.lcm, Pump Mode : Binary gradient, Conc. of Pump B : 30.0%, Oven Temperature: 250C, Instrument Name : Shimadzu LC-20AD, Mobile Phase A: n-Hexane / DCM=5 / 1, Mobile Phase B: MeOH / EtOH=1 / 1(0.1%DEA), Wavelength: from 190 nm to 500 nm.

[0524] This is the isomer eluted second and the chirality on carbon atom moiety of this isomer (t = 4.832 min) was assumed as S, this resulted in (1S)-6-chloro-N-[2,4-difluoro-3-(2- {[1-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide (31.5 mg, 39.38%) as off-white solid.

[0525] This is the isomer eluted first and the chirality on carbon atom moiety of this isomer (t = 3.798 min) was assumed as R, this resulted in (1R)-6-chloro-N-[2,4-difluoro-3-(2-{[1-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide (30 mg, 37.5%) as off-white solid.

[0526] LCMS of Compound 41: RT = 1.121 min, m / z 644.2 [M+H]+

[0527] 1H NMR of Compound 41: 1H NMR (300 MHz, Methanol-d4) δ 9.06 (s, 1H), 7.69 (s, 1H), 7.60 (s, 4H), 7.45 (td, J = 8.9, 5.7 Hz, 1H), 7.15 – 7.02 (m, 1H), 5.15 (t, J = 6.8 Hz, 1H), 3.60 (t, J = 5.6 Hz, 2H), 3.38 (s, 3H), 3.31 – 3.18 (m, 1H), 3.10 (d, J = 11.9 Hz, 3H), 2.95 (dt, J = 17.0, 8.1 Hz, 1H), 2.73 (t, J = 5.6 Hz, 2H), 2.42 (t, J = 11.2 Hz, 3H), 2.12 (d, J = 12.8 Hz, 2H), 1.90 (dt, J = 13.6, 6.7 Hz, 1H), 1.75 (t, J = 10.8 Hz, 2H). Example S-35: N-[3-(8-ethyl-2-{[4-(methylamino)cyclohexyl]amino}quinazolin-6-yl)-2,4- difluorophenyl]-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 42) Br F

[0528] Into a 40 mL vial were added 6-bromo-8-ethyl-2-fluoroquinazoline (500 mg, 1.960 mmol, 1 equiv), benzyl N-methyl-N-[(1r,4r)-4-aminocyclohexyl]carbamate (771.35 mg, 2.940 mmol, 1.5 equiv), DIEA (1520.02 mg, 11.760 mmol, 6.0 equiv) and n-BuOH (5 mL) at 130 °C for 2h. The crude product was purified by reverse phase flash with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 60.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. The collected fractions were combined and concentrated under vacuum.) To afford benzylN-methyl-N-[(1r,4r)-4-[(6- bromo-8-ethylquinazolin-2-yl)amino]cyclohexyl]carbamate (700 mg, 71.79%) as a light brown solid.

[0529] LCMS: m / z 497.4 [M+H]+O OCbz B B

[0530] Into a 40 ml vial were added benzyl N-methyl-N-[(1r,4r)-4-[(6-bromo-8- ethylquinazolin-2-yl)amino]cyclohexyl]carbamate (700 mg, 1.407 mmol, 1 equiv) and bis(pinacolato)diboron (714.70 mg, 2.814 mmol, 2.0 equiv) in dioxane (7 mL) was added KOAc (276.21 mg, 2.814 mmol, 2.0 equiv), Pd(dppf)Cl2 (51.48 mg, 0.070 mmol, 0.05 equiv) under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 100 mL). The filtrate was concentrated under reduced pressure. The crude product was re-crystallized from MTBE / MeOH (5 / 1) to afford benzyl N-methyl-N- [(1r,4r)-4-{[8-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2- yl]amino}cyclohexyl]carbamate (700 mg, 91.36%) as a black solid.

[0531] LCMS: RT = 1.591 min, m / z 545.3 [M+H]+OH5

[0532] Into a 8 mL vial were added benzyl N-methyl-N-[(1r,4r)-4-{[8-ethyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}cyclohexyl]carbamate (116.07 mg, 0.213 mmol, 1.5 equiv), N-(3-bromo-2,4-difluorophenyl)-6-fluoro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (60 mg, 0.142 mmol, 1.00 equiv), K2CO3 (58.92 mg, 0.426 mmol, 3.0 equiv), Pd(dppf)Cl2(5.20 mg, 0.007 mmol, 0.05 equiv), dioxane (1 mL) and H2O (0.1 mL) under nitrogen atmosphere at 100oC for 16h.The crude product was purified by reverse phase flash with the following conditions (Prep-HPLC- 013:Column,SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05%FA) and MeCN (22.0% MeCN up to 60.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. The collected fractions were combined and concentrated under vacuum.) to afford benzyl N-[4-({6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamido)phenyl]-8-ethylquinazolin-2-yl}amino)cyclohexyl]-N-methylcarbamate (30 mg, 27.78%) as a light brown solid.

[0533] LCMS: RT = 1.046 min, m / z 760.2 [M+H]+F F O Cbz CF35 6

[0534] Into a 8 ml vial, was placed benzyl N-[4-({6-[2,6-difluoro-3-(6-fluoro-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamido)phenyl]-8-ethylquinazolin-2- yl}amino)cyclohexyl]carbamate (30 mg, 0.040 mmol, 1 equiv), TFA (1 mL, 13.463 mmol, 334.70 equiv). The resulting solution was stirred for 1h at 50oC. The resulting mixture was concentrated under vacuum. This resulted in 4-{[3-(8-ethyl-2-{[4- (methylamino)cyclohexyl]amino}quinazolin-6-yl)-2,4-difluorophenyl]sulfamoyl}-6-fluoro- 2,3-dihydro-1H-inden-1-yl 2,2,2-trifluoroacetate (25 mg, 86.12%) as a light brown solid.

[0535] LCMS: m / z 721.7 [M+H]+OH6

[0536] Into a 8 ml vial, was placed 4-{[3-(8-ethyl-2-{[4- (methylamino)cyclohexyl]amino}quinazolin-6-yl)-2,4-difluorophenyl]sulfamoyl}-6-fluoro- 2,3-dihydro-1H-inden-1-yl 2,2,2-trifluoroacetate (25 mg, 0.035 mmol, 1 equiv), K2CO3 (14.36 mg, 0.105 mmol, 3.0 equiv), MeOH (1 mL) . The resulting solution was stirred for 1 h at rt. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18OBD Column, 19*150mm 5um; mobile phase, Water (0.5% FA) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in N-[3-(8-ethyl-2-{[4-(methylamino)cyclohexyl]amino}quinazolin-6-yl)-2,4- difluorophenyl]-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (6.4 mg, 29.41%) as a off-white solid.

[0537] LCMS: RT = 1.245 min, m / z 626.3 [M+H]+

[0538] 1H NMR:1H NMR (300 MHz,CD3OD) δ 9.01 (s, 1H), 8.57 (s, 1H), 7.54 (s, 1H), 7.50 – 7.28 (m, 4H), 7.06 (t, J = 9.3 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.00 (s, 2H), 3.11 – 3.00 (m, 3H), 2.71 (s, 4H), 2.45 (s, 1H), 2.37 (s, 2H), 2.23 (s, 2H), 1.89 (dd, J = 13.4, 7.1 Hz, 1H), 1.52 (q, J = 11.0 Hz, 5H), 1.33 (t, J = 7.4 Hz, 4H). Example S-36: N-[2,4-difluoro-3-(2-{[4-(methylamino)cyclohexyl]amino}quinazolin-6- yl)phenyl]-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 43) Cbz BrClStep1 1 3

[0539] Into a 40 ml vial, was placed 6-bromo-2-chloroquinazoline (500 mg, 2.053 mmol, 1 equiv), benzyl N-(4-aminocyclohexyl)-N-methylcarbamate (1080 mg, 4.117 mmol, 2.00 equiv), n-BuOH (5 mL), DIEA (1600 mg, 12.379 mmol, 6.03 equiv). The resulting solution was stirred for 2 h at 130oC. The resulting mixture was extracted with EA (3 x 100ml). The combined organic layers were washed with brine.aq (3 x 100 ml), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue in benzyl N-{4-[(6-bromoquinazolin-2-yl)amino]cyclohexyl}-N-methylcarbamate (650 mg, 33.72%) was applied on a silica gel column and eluted with ethyl acetate / hexane (1 / 5) to give 650 mg product as a off-white solid.

[0540] LCMS: m / z 469.3 [M+H]+O OCb

[0541] Into a 40 mL vial, was placed benzyl N-{4-[(6-bromoquinazolin-2- yl)amino]cyclohexyl}-N-methylcarbamate (650 mg, 1.385 mmol, 1 equiv), bis(pinacolato)diboron (703.31 mg, 2.770 mmol, 2 equiv), Pd(dppf)Cl2(50.66 mg, 0.069 mmol, 0.05 equiv), KOAc (339.77 mg, 3.462 mmol, 2.5 equiv), dioxane (6.5 mL, 76.726 mmol, 55.41 equiv). The resulting mixture was stirred for 2 h at 90oC. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting solution was extracted with 3 x 50 mL of ethyl acetate concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1 / 4). The collected fractions were combined and concentrated under vacuum. This resulted in benzyl N-methyl-N-(4-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinazolin-2-yl]amino}cyclohexyl) carbamate (800 mg, 67.12%) as a light yellow solid.

[0542] LCMS: RT = 1.568 min, m / z 517.4 [M+H]+C NOH56

[0543] Into a 8 mL vial, was placed benzyl N-methyl-N-(4-{[6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}cyclohexyl)carbamate (60 mg, 0.116 mmol, 1 equiv), N-(3-bromo-2,4-difluorophenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (55 mg, 0.130 mmol, 1.12 equiv), Pd(dppf)Cl2(5 mg, 0.007 mmol, 0.06 equiv), K2CO3 (50 mg, 0.362 mmol, 3.11 equiv), dioxane (1 mL, 11.804 mmol, 101.60 equiv), H2O (0.1 mg, 0.006 mmol, 0.05 equiv). The resulting mixture was stirred for 16 h at 100oC. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure The resulting solution was extracted with 3 x 50 mL of ethyl acetateconcentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1 / 4). The collected fractions were combined and concentrated under vacuum. This resulted in benzyl N-[4-({6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamido)phenyl]quinazolin-2-yl}amino)cyclohexyl]-N-methylcarbamate (40 mg, 42.34%) as a off-white solid.

[0544] LCMS: RT = 1.268 min, m / z 732.1 [M+H]+F F CbzO O O ON OH

[0545] Into a 8 ml vial, was placed benzyl N-[4-({6-[2,6-difluoro-3-(6-fluoro-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamido)phenyl]quinazolin-2-yl}amino)cyclohexyl]-N- methylcarbamate (40 mg, 0.055 mmol, 1 equiv), TFA (0.5 mL, 6.732 mmol, 123.15 equiv). The resulting solution was stirred for 2 h at 60oC. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (column, C18 silica gel; mobile phase, water (0.5% NH3.H2O) in ACN, 30% to 98% gradient in 10 min; detector, UV 254 nm. ). To afford N-[2,4-difluoro-3-(2-{[4- (methylamino)cyclohexyl]amino}quinazolin-6-yl)phenyl]-6-fluoro-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamide (8.1 mg, 24.22%) as a white solid.

[0546] LCMS: RT = 1.170 min, m / z 598.3 [M+H]+

[0547] 1H NMR:1H NMR (300 MHz, CD3OD) δ 9.09 (s, 1H), 7.72 (s, 1H), 7.61 (d, J = 4.4 Hz, 2H), 7.57 – 7.39 (m, 1H), 7.50 – 7.21 (m, 1H), 7.11 (t, J = 8.5 Hz, 1H), 5.15 (t, J = 6.7 Hz, 1H), 4.01 (s, 1H), 2.75 (s, 3H), 2.28 (s, 5H), 1.95 – 1.85 (m, 1H), 1.55 (s, 5H). Example S-37: N-(2,4-difluoro-3-{2-[(1-methylpiperidin-3-yl)amino]quinazolin-6- yl}phenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 44)BrCl

[0548] Into a 8 mL vial were added 6-bromo-2-chloroquinazoline (300 mg, 1.232 mmol, 1 equiv), n-BuOH (3 mL), tert-butyl 3-aminopiperidine-1-carboxylate (370.15 mg, 1.848 mmol, 1.5 equiv), DIEA (955.46 mg, 7.392 mmol, 6.0 equiv) at 130oC for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was washed with petroleum ether (3x5ml). The resulting mixture was concentrated under vacuum. To afford tert-butyl 3- [(6-bromoquinazolin-2-yl)amino]piperidine-1-carboxylate (380 mg, 75.72%) as a light yellow solid.

[0549] LCMS: RT = 1.236 min, m / z 409.2 [M+H]+B3 5

[0550] Into a 8-mL vial was placed tert-butyl 3-[(6-bromoquinazolin-2- yl)amino]piperidine-1-carboxylate, bis (pinacolato)diboron, Pd(dppf)Cl2, KOAc, dioxane. The resulting solution was stirred for 2 h at 90 °C. The crude product was purified by Prep- HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 70 mL / min; Detector, UV 220nm. The solvent was evaporated in vacuo to give yellow syrup.

[0551] LCMS: m / z 454.4 [M+H]+O O B

[0552] Into a 8-mL vial was placed tert-butyl 3-{[6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1-carboxylate, HCl, DCM. The resulting solution was stirred for 2 h at 20 °C . The solvent was evaporated in vacuo to give yellow syrup.

[0553] LCMS: m / z 354.3 [M+H]+H

[0554] Into a 8 mL vial were added N-(piperidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-2-amine (170 mg, 0.480 mmol, 1 equiv), K2CO3 (132.64 mg, 0.960 mmol, 2.0 equiv), DMF (2 mL), CH3I (40.87 mg, 0.288 mmol, 0.6 equiv) at room temperature for 2 h. The crude product was purified by reverse phase flash with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 60.0% in 7 min) to afford N-(1-methylpiperidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin- 2-amine (70 mg, 39.61%) as a light yellow solid.

[0555] LCMS: m / z 368.3 [M+H]+F OOOH N

[0556] Into a 8 mL vial were added N-(1-methylpiperidin-3-yl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (70 mg, 0.190 mmol, 1 equiv), N-(3-bromo-2,4- difluorophenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (120.38 mg, 0.285 mmol, 1.5 equiv), K2CO3 (78.80 mg, 0.570 mmol, 3.0 equiv), dioxane (1 mL), H2O (0.1 mL) and Pd(dppf)Cl2(6.95 mg, 0.010 mmol, 0.05 equiv) at 100oC for 16 h. The crude product was purified by reverse phase flash with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 60.0% in 7 min). Lyophilization. To afford N- (2,4-difluoro-3-{2-[(1-methylpiperidin-3-yl)amino]quinazolin-6-yl}phenyl)-6-fluoro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (17.7 mg, 15.76%) as a off white solid.

[0557] LCMS: RT = 1.270 min, m / z 584.2 [M+H]+

[0558] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 7.71 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.48 – 7.36 (m, 2H), 7.36 – 7.30 (m, 1H), 7.09 – 7.00 (m, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.27 (dt, J = 9.7, 5.2 Hz, 1H), 3.24 (dt, J = 8.8, 4.1 Hz, 1H), 3.11 (s, 1H), 2.93 (dt, J = 16.6, 7.9 Hz, 1H), 2.76 (s, 1H), 2.46 (ddt, J = 15.3, 7.7, 3.9 Hz, 1H), 2.35 (s, 3H), 2.19 (s, 2H), 2.02 (s, 1H), 1.96 – 1.81 (m, 2H), 1.79 – 1.68 (m, 0H), 1.47 (d, J = 11.6 Hz, 1H). Example S-38: 1-amino-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-6-chloro-2,3- dihydro-1H-indene-4-sulfonamide (Compound 45)F F OO O OBrO

[0559] Into a 40-mL vial, was placed N-(3-bromo-2,4-difluorophenyl)-6-chloro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (720 mg, 1 Eq, 1.64 mmol) and Bu4N+BF4- (54.0 mg, 0.1 Eq, 164 μmol) in ACN (4 mL) and H2O (4 mL). The resulting reaction mixture was stirred for 16 hours at 25 °C. The mixture was directly purified by MPLC with the following conditions: Column, WelFlashTM, C18120 g, Spherical 20-40 μm; Mobile phase, Water (0.05% FA) and ACN (5% ACN to 5% ACN in 2 min, 30% ACN up to 98% in 12 min, 98% ACN to 98% in 1 min); Total flow rate, 70 mL / min; Detector, UV 220 nm. The collected fractions were dried by lyophilization. The resulted in N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-oxo-2,3-dihydro-1H-indene-4-sulfonamide (160 mg, 366 μmol, 22.3 %) as a white solid.

[0560] LCMS: RT = 1.215 min, m / z 433.8, 435.8 [M-H]- F HBr2 3

[0561] Into a 8 mL vial were added N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-oxo-2,3- dihydroindene-4-sulfonamide (140 mg, 0.321 mmol, 1 equiv), pyridine (101.45 mg, 1.284 mmol, 4 equiv), Hydroxylamine hydrochloride (89.12 mg, 1.284 mmol, 4 equiv) and EtOH (2 mL) for 16 h at 25 ℃. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (1E)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-(hydroxyimino)-2,3-dihydroindene-4- sulfonamide (145 mg, 100.13%) as a off-white solid.

[0562] LCMS: RT = 1.197 min, m / z 448.8, 450.8 [M-H]-F F OOOHO OBrH2

[0563] Into a 8mL vial were added (1E)-N-(3-bromo-2,4-difluorophenyl)-6-chloro-1- (hydroxyimino)-2,3-dihydroindene-4-sulfonamide (100 mg, 0.221 mmol, 1 equiv), molybdenum trioxide (47.81 mg, 0.332 mmol, 1.5 equiv), NaBH4 (25.13 mg, 0.663 mmol, 3 equiv) and MeOH (1 mL) for 16 h at 25 ℃. The reaction was quenched with sodium bicarbonate solution at 25 ℃. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated salt solution (50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-amino-N-(3-bromo-2,4- difluorophenyl)-6-chloro-2,3-dihydro-1H-indene-4-sulfonamide (72 mg, 74.30%) as a off- white solid.

[0564] LCMS: RT = 0.893 min, m / z 434.6, 436.6 [M-H]- ocB4 5

[0565] Into a 8 mL vial were added 1-amino-N-(3-bromo-2,4-difluorophenyl)-6-chloro- 2,3-dihydro-1H-indene-4-sulfonamide (50 mg, 0.114 mmol, 1 equiv), di-tert-butyl dicarbonate (74.80 mg, 0.342 mmol, 3 equiv), TEA (23.12 mg, 0.228 mmol, 2 equiv) and DCM (1 mL) for 16 h at 25 ℃. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water in acetonitrile, 30% to 98% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl N-{4-[(3-bromo-2,4-difluorophenyl)sulfamoyl]-6-chloro-2,3-dihydro-1H-inden-1- yl}carbamate (60 mg, 97.66%) as a off-white solid.

[0566] LCMS: RT = 1.413 min, m / z 534.8, 536.8 [M-H]- O F BocBr

[0567] Into a 8 mL vial were added tert-butyl N-{4-[(3-bromo-2,4- difluorophenyl)sulfamoyl]-6-chloro-2,3-dihydro-1H-inden-1-yl}carbamate (55 mg, 0.102 mmol, 1 equiv), 2-ammonio-6-(4,4,5,5-tetramethyliumyl-1,3,2lambda4-dioxaborolane- 1,3,4,5-tetraium-2-ylium-2-yl)quinazoline-1,2,3-triium-4,5,6,7,8,4a,8a-heptakis(ylium) (82.25 mg, 0.306 mmol, 3 equiv) , Pd(dppf)Cl2 (3.74 mg, 0.005 mmol, 0.05 equiv), K2CO3 (42.40 mg, 0.306 mmol, 3 equiv), dioxane (1 mL) and H2O (0.2 mL) for 16 h at 100 ℃. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water in acetonitrile, 30% to 98% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl N-(4-{[3-(2-aminoquinazolin-6-yl)-2,4- difluorophenyl]sulfamoyl}-6-chloro-2,3-dihydro-1H-inden-1-yl)carbamate (30 mg, 48.72%) as a off-white solid.

[0568] LCMS: RT = 1.273 min, m / z 602.1 [M+H]+H2H27

[0569] Into a 8 mL vial were added tert-butyl N-(4-{[3-(2-aminoquinazolin-6-yl)-2,4- difluorophenyl]sulfamoyl}-6-chloro-2,3-dihydro-1H-inden-1-yl)carbamate (30 mg, 0.050 mmol, 1 equiv), DCM (1 mL) and TFA (0.2 mL) for 2 h at 20 ℃. The crude product (25 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3·H2O)and MeCN (22.0% MeCN up to 60.0% in 7 min) to afford 1-amino-N-[3-(2- aminoquinazolin-6-yl)-2,4-difluorophenyl]-6-chloro-2,3-dihydro-1H-indene-4-sulfonamide (4.2 mg, 16.79%) as a White transparent solution. This resulted in 1-amino-N-[3-(2- aminoquinazolin-6-yl)-2,4-difluorophenyl]-6-chloro-2,3-dihydro-1H-indene-4-sulfonamide (4.2 mg, 16.79%) as a off-white solid.

[0570] LCMS: RT = 1.036 min, m / z 502.2 [M+H]+

[0571] 1H NMR:1H NMR (400 MHz, Methanol-d4) δ 9.12 (s, 1H), 7.80 (s, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.42 – 7.32 (m, 1H), 6.98 (t, J = 9.2 Hz, 1H), 4.36 (t, J = 7.6 Hz, 1H), 2.99 (dt, J = 17.3, 8.6 Hz, 1H), 1.85 – 1.71 (m, 1H), 1.31 (s, 1H) Example S-39: N-{2,4-difluoro-3-[2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-6- fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 48) Br O

[0572] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was 4-bromo-6-fluoro-2,3-dihydroinden-1-one (3.0 g, 13.098 mmol, 1 equiv), benzyl mercaptan (1.79 g, 14.408 mmol, 1.1 equiv), Pd2(dba)3 (0.60 g, 0.655 mmol, 0.05 equiv), Xantphos (0.76 g, 1.310 mmol, 0.1 equiv) and DIEA (5.08 g, 39.294 mmol, 3.0 equiv), dioxane (30 mL). The resulting solution was stirred under nitrogen atmosphere at 100oC for 16 h. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (20 / 80), The collected fractions were combined and concentrated under vacuum. This resulted in 4-(benzylsulfanyl)-6-fluoro-2,3-dihydroinden-1-one (2.5 g, 70.09%) as a light yellow solid.

[0573] LCMS: m / z 272.3 [M+H]+O ONCSSO AcOH, Ho2O,0 C~RT, 2 h step24

[0574] Into a 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(benzylsulfanyl)-6-fluoro-2,3-dihydroinden-1-one (1.5 g, 5.508 mmol, 1 equiv), NCS (2.21 g, 16.524 mmol, 3 equiv), AcOH (15 mL) and H2O (1.5 mL). The resulting solution was stirred for 16 h at rt. Adjusted to pH 6~7 with sodium bicarbonate. The resulting mixture was extracted with EA (3 x 20ml). The combined organic layers were washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue in 6-fluoro-1-oxo-2,3- dihydroindene-4-sulfonyl chloride (2 g, crude) as a light yellow solid.

[0575] LCMS: m / z 248.7 [M+H]+OClO

[0576] Into a 50 mL round-bottom flask purged and maintained, was placed 6-fluoro-1- oxo-2,3-dihydroindene-4-sulfonyl chloride (1.5 g, 6.033 mmol, 1 equiv), Pyridine, 6.0 equiv), DCM (15 mL), 3-bromo-2,4-difluoroaniline (1.88 g, 9.050 mmol, 1.5 equiv). The resulting solution was stirred for 16 h at rt. The resulting mixture was extracted with EA (3 x 20ml). dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue in N-(3-bromo-2,4-difluorophenyl)-6-fluoro-1-oxo-2,3- dihydroindene-4-sulfonamide (900 mg, 35.50%) was applied on a silica gel column and eluted with ethyl acetate / hexane (1 / 5) to give 900 mg product as a brown yellow solid.

[0577] LCMS: m / z 420.2 [M+H]+F F OO O OBrH

[0578] Into a 50 mL round-bottom flask purged, was placed N-(3-bromo-2,4- difluorophenyl)-6-fluoro-1-oxo-2,3-dihydroindene-4-sulfonamide (900 mg, 2.142 mmol, 1 equiv), NaBH4(162.05 mg, 4.284 mmol, 2.0 equiv), MeOH (9 mL). The resulting solution was stirred for 16 h at rt. Adjusted to pH 6~7 with sodium bicarbonate. The resulting mixture was extracted with EA (3 x 20ml). The combined organic layers were washed with NaCl.aq (3 x 20 ml), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue in N-(3-bromo-2,4-difluorophenyl)-6- fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (830 mg, 91.78%) was applied on a silica gel column and eluted with ethyl acetate / hexane (1 / 5) to give 830 mg product as a off- white solid.

[0579] LCMS: m / z 422.2 [M+H]+FBr OH78

[0580] Into a 8 mL vial were added N-(3-bromo-2,4-difluorophenyl)-6-fluoro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (100 mg, 0.237 mmol, 1 equiv), tert-butyl 4- {[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1- carboxylate (161.43 mg, 0.355 mmol, 1.5 equiv), K2CO3(98.20 mg, 0.711 mmol, 3.0 equiv), dioxane (1 mL), H2O (0.1 mL) and Pd(dppf)Cl2 (8.67 mg, 0.012 mmol, 0.05 equiv) at 100 ℃ for 16 h. The crude product was purified by Prep-HPLC with the following conditions (Prep- HPLC-013: Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.05% NH3.H2O) and MeCN (22.0% MeCN up to 60.0% in 7 min) to afford tert-butyl 4-({6- [2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)phenyl]quinazolin-2-yl}amino)piperidine-1-carboxylate (90 mg, 56.74%) as a light brown solid.

[0581] LCMS: RT = 1.512 min, m / z 670.2 [M+H]+F F OO O OBo OH

[0582] Into a 8-mL vial was placed tert-butyl 4-({6-[2,6-difluoro-3-(6-fluoro-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamido)phenyl]quinazolin-2-yl}amino)piperidine-1- carboxylate (90 mg, 0.134 mmol, 1 equiv), trifluoroacetaldehyde (0.2 mL) , DCM (1 mL). The resulting solution was stirred for 2 h at rt. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.1% FA) and ACN (5.0% ACN up to 95.0% in 6 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in N- {2,4-difluoro-3-[2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-6-fluoro-1-hydroxy-2,3- dihydro-1H-indene-4-sulfonamide (36 mg, 46.09%) as a off white solid.

[0583] LCMS: RT = 2.710 min, m / z 570.2 [M+H]+

[0584] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.50 – 7.34 (m, 2H), 7.36 – 7.27 (m, 1H), 6.99 (t, J = 9.3 Hz, 1H), 5.14 (t, J = 6.8 Hz, 1H), 4.24 – 4.14 (m, 1H), 3.30 (s, 1H), 2.97 (dt, J = 24.2, 10.0 Hz, 3H), 2.46 (ddt, J = 16.9, 7.7, 3.9 Hz, 1H), 2.23 (d, J = 13.1 Hz, 2H), 1.90 (ddd, J = 21.2, 14.9, 7.5 Hz, 1H), 1.74 (d, J = 10.5 Hz, 1H), 1.68 (d, J = 13.8 Hz, 1H). Example S-40: 6-chloro-N-{2,4-difluoro-3-[2-(piperidin-4-ylamino)quinazolin-6- yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (Compound 49)Br O

[0585] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-6-chloro-2,3-dihydroinden-1-one (3.0 g, 12.220 mmol, 1 equiv), benzyl mercaptan (1.67 g, 13.442 mmol, 1.1 equiv), Pd2(dba)3 (0.56 g, 0.611 mmol, 0.05 equiv), Xantphos (0.71 g, 1.222 mmol, 0.1 equiv) and DIEA (4.74 g, 36.660 mmol, 3.0 equiv), dioxane (30 mL). The resulting solution was stirred under nitrogen atmosphere at 100 °C for 16 h. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1 / 4). The collected fractions were combined and concentrated under vacuum. This resulted in 4-(benzylsulfanyl)-6-chloro-2,3-dihydroinden-1-one (2.3 g, 46.27%) as a light brown solid.

[0586] LCMS: m / z 288.8 [M+H]+O3

[0587] Into a 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(benzylsulfanyl)-6-chloro-2,3-dihydroinden-1-one (1.5 g, 5.194 mmol, 1 equiv), NCS (2.08 g, 15.582 mmol, 3.0 equiv), AcOH (15 mL) and H2O (3 mL). The resulting solution was stirred for 16 h at rt. Adjusted to pH 6~7 with sodium bicarbonate. The resulting mixture was extracted with EA (3 x 20ml). The combined organic layers were washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue in 6-chloro-1-oxo-2,3- dihydroindene-4-sulfonyl chloride (1.9 g, 137.99%) was applied on a silica gel column and eluted with ethyl acetate / hexane (1 / 5) to give 1.9 g product as a light yellow solid.

[0588] LCMS: m / z 265.1 [M+H]+FOO Cl

[0589] Into a 50 mL round-bottom flask purged and maintained, was placed 6-chloro-1- oxo-2,3-dihydroindene-4-sulfonyl chloride (1.5 g, 5.658 mmol, 1 equiv), Pyridine (2.69 g, 33.948 mmol, 6.0 equiv), DCM (15 mL), 3-bromo-2,4-difluoroaniline (1.77 g, 8.487 mmol, 1.5 equiv). The resulting solution was stirred for 16 h at rt. The resulting mixture was extracted with EA (3 x 20ml), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue in N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-oxo-2,3-dihydroindene-4-sulfonamide (1.0 g, 40.47%) was applied on a silica gel column and eluted with ethyl acetate / hexane (1 / 5) to give 1 g product as a brown yellow solid.

[0590] LCMS: m / z 436.7 [M+H]+FBH67

[0591] Into a 50 mL round-bottom flask purged, was placed N-(3-bromo-2,4- difluorophenyl)-6-chloro-1-oxo-2,3-dihydroindene-4-sulfonamide (1.0 g, 2.290 mmol, 1 equiv), NaBH4 (173.27 mg, 4.580 mmol, 2.0 equiv), MeOH (10 mL). The resulting solution was stirred for 16 h at rt. Adjusted to pH 6~7 with sodium bicarbonate. The resulting mixture was extracted with EA (3 x 20ml). The combined organic layers were washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue in N-(3-bromo-2,4-difluorophenyl)-6-chloro-1-hydroxy- 2,3-dihydro-1H-indene-4-sulfonamide (900 mg, 89.59%) was applied on a silica gel column and eluted with ethyl acetate / hexane (1 / 5) to give 900 mg product as a off-white solid.

[0592] LCMS: m / z 438.7 [M+H]+Boc N BrCl

[0593] Into a 100 mL round-bottom flask ,were added 6-bromo-2-chloroquinazoline (2 g, 8.214 mmol, 1 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (2.47 g, 12.321 mmol, 1.5 equiv), DIEA (6.37 g, 49.284 mmol, 6.0 equiv ) and n-BuOH (20 mL), the reaction mixture was stirred for 4 h at 130oC. After completion of reaction, the reaction mixture was quenched by addition of water 200 ml. The aqueous layer was extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with brine (100 ml x 3). dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product. Then the residue was purified by trituration with petroleum ether (300 ml). The precipitated solids were collected by filtration. To afford tert-butyl 4-[(6-bromoquinazolin-2- yl)amino]piperidine-1-carboxylate (3.5 g crude) as a gray solid.

[0594] LCMS: m / z 407.3 [M+H]+Bostep8

[0595] Into a 1000-mL round-bottom flask, and maintained with an inert atmosphere of nitrogen, we added tert-butyl 4-[(6-bromoquinazolin-2-yl)amino]piperidine-1-carboxylate (3.5 g, 8.593 mmol, 1 equiv), bis(pinacolato)diboron (3.27 g, 12.889 mmol, 1.5 equiv), KOAc (1.69 g, 17.186 mmol, 2.0 equiv), dioxane (35 mL), Pd(dppf)Cl2 (0.31 g, 0.430 mmol, 0.05 equiv). The reaction mixture was stirred for 4 h at 90oC. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). To afford tert-butyl 4-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1-carboxylate (3.8 g, 97.32%) as a light yellow solid.

[0596] LCMS: m / z 454.3 [M+H]+FBrOH78

[0597] Into a 8 mL vial, was placed N-(3-bromo-2,4-difluorophenyl)-6-chloro-1- hydroxy-2,3-dihydro-1H-indene-4-sulfonamide (100 mg, 0.228 mmol, 1 equiv), tert-butyl 4- {[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl]amino}piperidine-1- carboxylate (155.37 mg, 0.342 mmol, 1.5 equiv), Pd(dppf)Cl2(8.34 mg, 0.011 mmol, 0.05 equiv), K2CO3 (94.52 mg, 0.684 mmol, 3.0 equiv), dioxane (1 mL, 11.804 mmol, 51.78 equiv) and H2O (0.1 mL, 5.551 mmol, 24.35 equiv). The resulting mixture was stirred for 16 h at 90oC under nitrogen atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.5% NH4HCO3) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in tert-butyl 4-({6-[3-(6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)-2,6- difluorophenyl]quinazolin-2-yl}amino)piperidine-1-carboxylate (80 mg, 51.14%) as a light yellow solid.

[0598] LCMS: RT = 1.527 min, m / z 686.2 [M+H]+BoOH8

[0599] Into a 8 ml vial, was placed tert-butyl 4-({6-[3-(6-chloro-1-hydroxy-2,3-dihydro- 1H-indene-4-sulfonamido)-2,6-difluorophenyl]quinazolin-2-yl}amino)piperidine-1- carboxylate (80 mg, 0.117 mmol, 1 equiv), trifluoroacetaldehyde (0.2 mL), DCM (1 mL). The resulting solution was stirred for 1 h at rt. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep- HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water (0.5% FA) and ACN (5.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL / min; Detector, UV 220nm. Lyophilization. This resulted in 6-chloro-N-{2,4-difluoro-3-[2- (piperidin-4-ylamino)quinazolin-6-yl]phenyl}-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (22.8 mg, 31.70%) as a off-white solid.

[0600] LCMS: RT = 2.335 min, m / z 586.2 [M+H]+

[0601] 1H NMR:1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 7.74 (s, 1H), 7.69 – 7.62 (m, 2H), 7.62 – 7.53 (m, 2H), 7.38 (td, J = 9.0, 5.8 Hz, 1H), 7.00 (t, J = 9.3 Hz, 1H), 5.15 (t, J = 6.8 Hz, 1H), 4.25 – 4.16 (m, 1H), 3.08 – 2.91 (m, 3H), 2.46 (ddd, J = 15.7, 8.0, 3.9 Hz, 1H), 2.24 (d, J = 13.1 Hz, 2H), 1.98 – 1.82 (m, 1H), 1.76 (d, J = 10.4 Hz, 1H), 1.71 (d, J = 9.9 Hz, 1H). Example S-41: (1R)-6-chloro-N-(3-{8-ethyl-2-[(1-methylpiperidin-4- yl)amino]quinazolin-6-yl}-2,4-difluorophenyl)-1-hydroxy-2,3-dihydro-1H-indene-4- sulfonamide (Compound 50)1 step 1 2

[0602] In a 500-mL round bottom flask to a solution of i-Pr2NH (12.96 g, 128.045 mmol, 1.3 equiv) in THF (100 mL) was added dropwise n-BuLi (7.57 g, 118.195 mmol, 1.2 equiv) solution in THF at -30 °C under N2 atmosphere. The reaction mixture was stirred at -30°C for 30 mins. Then a solution of 4-bromo-2-ethyl-1-fluorobenzene (20 g, 98.496 mmol, 1 equiv) in 50 mL THF was added dropwise and the mixture was stirred for another 60mins at -78°Cto -50°C. Then a solution of DMF (14.40 g, 196.992 mmol, 2 equiv) in 50 mL THF was added dropwise and the mixture was stirred for another 2 h at -78°C to rt. The reaction was quenched with NH4Cl(300 mL), and then the mixture was extracted with ether / EtOAc (2*150mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to 5-bromo-3-ethyl-2- fluorobenzaldehyde (12.5 g, 54.92%) .

[0603] LCMS: m / z 231 [M+H]+NH r O

[0604] Into a 250-mL vial was placed with a mixture of 5-bromo-3-ethyl-2- fluorobenzaldehyde (12.5 g, 54.098 mmol, 1 equiv), guanidine (4.79 g, 81.147 mmol, 1.5 equiv), DIEA (20.98 g, 162.294 mmol, 3 equiv), DMAc (130mL). The reaction mixture was stirred at 90°C-160°C for 2 h. The resulting mixture was extracted with EA (3 x 100mL). The combined organic layers were washed with NaCl dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 6-bromo-8- ethylquinazolin-2-amine (2.2 g, 16.13%) as a white solid.

[0605] LCMS: m / z 252 [M+H]+. r t-butyl nitrite, PyHF H2-20oC to rt, 16 h3step 3 4

[0606] Into a 100-mL round-bottom flask was placed 6-bromo-8-ethylquinazolin-2-amine (2.23 g, 8.845 mmol, 1 equiv), Pyridine (20 mL). This was followed by the addition of pyridine hydrofluoride (21.92 g, 221.125 mmol, 25 equiv) at -20 °C for 40 min. Then added tert-butyl nitrite (2.92 g, 28.304 mmol, 3.2 equiv). The temperature was increased to room temperature naturally. The resulting solution was stirred for 16 h at 25 °C. The resulting solution was extracted with 3x50 mL of EA concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate / petroleum ether (1 / 4). The collected fractions were combined and concentrated under vacuum. This resulted in 6-bromo-8-ethyl- 2-fluoroquinazoline (450 mg, 19.94%) as a light orange solid.

[0607] LCMS: m / z 255 [M+H]+Boc N BrFstep 4 45

[0608] Into a 20 mL vial was placed 6-bromo-8-ethyl-2-fluoroquinazoline (300 mg, 1.176 mmol, 1 equiv), DIEA (456.00 mg, 3.528 mmol, 3 equiv), DMSO (3mL), The resulting solution was stirred for 2 hour at 100°C, The crude...

Claims

CLAIMS 1. A compound according to Formula (I): R3R10R8R );or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C8cycloalkyl, C3-C8cycloalkenyl, C6-C14aryl, 3- to 12-membered heterocyclyl, and 5- to 10- membered heteroaryl are each independently optionally substituted by one or more RL; R2, R8, R9and R10are independently H, halo, C1-C6alkyl, or C1-C6alkoxy; R3, R4, R5, R6and R7are independently selected from the group consisting of H, halo, -OR11, C1-C6 alkyl, and C1-C6 alkoxy; X and Y are each independently CRaRb, C=O, or O, wherein Raand Rbare each independently H, halo, -OR11, -NR12R13, C1-C6alkyl optionally substituted by halo, or C1-C6alkoxy optionally substituted by halo; Rcis H or OH; n is 1 or 2; each RLis independently selected from the group consisting of halo, -OR11, C1-C6alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6- C14aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and -NR12R13, wherein the C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13; R11is H or C1-C6 alkyl optionally substituted by halo; and R12and R13, independently of each other and independently at each occurrence, are H or C1-C6alkyl optionally substituted by C1-C6alkoxy, halo, or -OH.

2. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is H, C1-C6alkyl, C3-C8cycloalkyl, C6-C14aryl, 3- to 12- membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by one or more RL.

3. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, R1is 3- to 12-membered heterocyclyl optionally substituted by one or more RL.

4. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is C3-C8 cycloalkyl optionally substituted by one or more RL.

5. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is H.

6. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting oRL, ,, , , andNRL.

7. The compound of any one of claim 1-6, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RLis halo, -OR11, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, 5- to 10-memberedheteroaryl, and -NR12R13, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C14 aryl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl are each independently optionally substituted by halo, -OH, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12- membered heterocyclyl, or -NR12R13.

8. The compound of any one of claim 1-6, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RLis C1-C6alkyl optionally substituted by halo, -OR11, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13.

9. The compound of any one of claim 1-6, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RLis -OH.

10. The compound of any one of claim 1-6, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RLis C3-C8 cycloalkyl optionally substituted by halo, -OH, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or - NR12R13.

11. The compound of any one of claim 1-6, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RLis 3- to 12-membered heterocyclyl optionally substituted by halo, -OH, C1-C6alkyl, C1-C6alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13.

12. The compound of any one of claim 1-6, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RLis 5- to 10-membered heteroaryl optionally substituted by halo, -OH, C1-C6 alkyl, C1-C6 alkoxy, 3- to 12-membered heterocyclyl, or -NR12R13.

13. The compound of any one of claim 1-6, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein RLis -NR12R13.

14. The compound of any one of claim 1-13, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R12and R13independently are H or C1-C6alkyl optionally substituted by C1-C6alkoxy.

15. The compound of any one of claim 1-14, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R2, R8, R9and R10are independently H, fluoro, methyl, ethyl, or methoxy.

16. The compound of any one of claim 1-15, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R3and R4are fluoro.

17. The compound of any one of claim 1-16, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R3is H and R4is fluoro.

18. The compound of any one of claim 1-17, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein R5, R6and R7are H, fluoro, chloro, OH, methyl or methoxy.

19. The compound of any one of claim 1-18, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein X is CRaRb, wherein Raand Rbare each independently H, -OH, -NH2, or C1-C6 alkyl.

20. The compound of any one of claim 1-18, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein X is CH2,CH(OH), C(OH)CH3, CH(NH2), C=O, or O.

21. The compound of any one of claim 1-20, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein Y is CRaRb, C=O or O.

22. The compound of any one of claim 1-20, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein Y is CH2, C(CH3)2, or O.

23. The compound of any one of claim 1-18, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein the moiety: nR6R7is selected from the group consisting of2OH Cl ,Cl,Cl,Cl,O O O O Cl, Cl Cl nd Cl24. The compound of any one of claim 1-18, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein the moietyis Cl.

25. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II): R1R6R7(II).

26. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIa):10 8F R ROR1.

27. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIa-1): F R1.

28. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIa-2): R1.

29. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III): RLR R (III).

30. The compound of claim 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIIa):10 8F R ROR .

31. A compound selected from the compounds in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

32. A compound selected from compounds 1-74 in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound of any one of claims 1-32, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

34. A method of treating a disease or disorder characterised by activation of GCN2 in an individual in need thereof, comprising administering to the individual a compound of any one of claims 1-32, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, wherein the disease or disorder is cancer, a neurodegenerative disease, or chronic infections.

36. The method of claim 35, wherein the disease or disorder is cancer.

37. The method of claim 36, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, cancer of secretory cells, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granularlymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia. small cell lung cancer, malignant pleural mesothelioma, Head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma or pediatric neuroblastoma.

38. The method of any one of claims 34-37, wherein the compound, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof is administered in combination with a second therapeutic agent, wherein the second therapeutic agent is PEG-arginase, asparaginase, anti-angiogenic factors, cysteinase or sulfasalazine.

39. The method of any one of claims 34-38, wherein the compound, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof decreases the activity of PERK.

40. The method of any one of claims 34-39, wherein the method comprises administering to the individual a therapeutically effective amount of the compound, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

41. The method of any one of claims 34-40, wherein the individual is a human.

42. A method of treating a cancer in an individual in need comprising administering a compound of any one of claims 1-32, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof to the individual, wherein the cancer has a low level of expression or activity of a urea cycle enzyme.

43. The method of claim 42, wherein the urea cycle enzyme is ASS1.

44. The method of claim 42 or 43, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, adenocarcinoma, hepatocellular carcinoma, thyroid cancer, multiple myeloma, cancer of secretory cells, myelodysplastic syndrome, myeloproliferative neoplasm, malignant glioma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granularlymphocytic leukemia, B-cell prolymphocytic leukemia, T-cell prolymphocytic leukemia. small cell lung cancer, malignant pleural mesothelioma, Head and neck squamous cell carcinoma, glioblastoma multiforme, sarcoma or pediatric neuroblastoma.

45. The method of any one of claims 42-44, wherein the compound, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof is administered in combination with a second therapeutic agent, wherein the second therapeutic agent is PEG-arginase, asparaginase, anti-angiogenic factors, cysteinase or sulfasalazine.

46. The method of any one of claims 42-45, wherein the compound, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof decreases the activity of PERK.

47. The method of any one of claims 42-46, wherein the method comprises administering to the individual a therapeutically effective amount of the compound, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.

48. The method of any one of claims 42-47, wherein the individual is a human.

49. Use of a compound of any one of claims 1-32, or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy.

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